piperidines and thioperamide

L-carnosine (β-alanyl-L-histidine; CAR) is synthesized in mammalian skeletal muscle. Although the physiological roles of CAR have not yet been clarified, there is evidence that the release of CAR from skeletal muscle during physical exercise affects autonomic neurotransmission and physiological functions. In particular, CAR affects the activity of sympathetic and parasympathetic nerves innervating the adrenal glands, liver, kidney, pancreas, stomach, and white and brown adipose tissues, thereby causing changes in blood pressure, blood glucose, appetite, lipolysis, and thermogenesis. CAR-mediated changes in neurotransmission and physiological functions were eliminated by histamine H1 or H3 receptor antagonists (diphenhydramine or thioperamide) and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN), a master circadian clock. Moreover, a carnosine-degrading enzyme (carnosinase 2) was shown to be localized to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN). Thus, CAR released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of CAR on neurotransmission and physiological function. Thus, CAR appears to influence hypoglycemic, hypotensive, and lipolytic activity through regulation of autonomic nerves and with the involvement of the SCN and histamine. These findings are reviewed and discussed in the context of other recent reports, including those on carnosine synthetases, carnosinases, and carnosine transport.

Topics: Animals; Autonomic Pathways; Blood Glucose; Blood Pressure; Carnosine; Circadian Clocks; Dipeptidases; Diphenhydramine; Histamine; Histamine H1 Antagonists; Histamine H3 Antagonists; Lipolysis; Piperidines; Rats; Suprachiasmatic Nucleus; Thermogenesis

We established a novel dermatitis model in mice earlobes and analyzed the roles of histamine using specific antagonists for histamine receptors. After sensitization with picryl chloride (PiCl) by painting it on the earlobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting with PiCl. Histamine antagonists and cyclosporin A were administered i.v. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response and increased the infiltration of eosinophils and mast cells at the inflammatory site. In this model, the PiCl-induced increase in the thickness of the earlobe in the immediate phase was suppressed by the histamine H₁ antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H₃/H₄ antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on TPA-modified contact dermatitis was as potent as that of cyclosporin A. Histamine plays significant roles in early-phase swelling via H₁ receptors and in late-phase swelling via H₃/H₄ receptors in this TPA-modified allergic dermatitis model.

Topics: Animals; Cyclosporine; Dermatitis, Atopic; Disease Models, Animal; Drug Therapy, Combination; Histamine; Histamine Antagonists; Humans; Mice; Picryl Chloride; Piperidines; Pyrilamine; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H3; Receptors, Histamine H4; Tetradecanoylphorbol Acetate

Topics: Animals; Humans; Piperidines; Receptors, Histamine; Receptors, Histamine H3

Histamine (HA) is synthesized from L-histidine by histidine decarboxylase (HDC), and HA released from neurons is predominantly methylated to tele-methylhistamine (t-MH), which is further metabolized by MAO. Therefore, the HA turnover rate is determined by either a exponential decrease in HA level after treatment with alpha-fluoromethylhistidine (alpha-FMH), a specific HDC inhibitor, or a linear accumulation of t-MH after pargyline treatment. Brain HA and t-MH can be simultaneously assayed using HPLC with fluorometric detection. Care should be given to avoid the contamination by extraencephalic mast-cell HA after microwave irradiation or immersion in liquid nitrogen, and to a marked circadian variation of t-MH level. The HA turnover is the highest in the hypothalamus, low in the pons-medulla oblongata and cerebellum, and nil in the spinal cord in rats, mice and guinea pigs. The half-life of neuronal HA is 8-87 min in various brain regions of these animals. Barbiturates, enflurane, benzodiazepines, GABA-mimetic drugs, ethanol and delta 9-tetrahydrocannabinol significantly decrease the HA turnover, whereas mu-opioid agonists such as morphine and [D-Ala2, MePhe4, Gly(ol)5] enkephalin enhance it. Foot-shock and phencyclidine also enhance it at least partly via mu-opioid receptors. Chlorpromazine, haloperidol, imipramine, methamphetamine or halothane have no influence on the HA turnover.

Topics: Anesthetics; Animals; Brain; Circadian Rhythm; Dronabinol; Ethanol; Half-Life; Histamine; Methylhistamines; Piperidines; Psychotropic Drugs

A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H. Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H. The treatment of H. These results highlight a novel interaction between the central histamine signaling and memory engrams.

Topics: Adult; Animals; Betahistine; Cognition; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Memory Disorders; Mental Recall; Mice; Mice, Inbred C57BL; Object Attachment; Perirhinal Cortex; Piperidines; Stochastic Processes; Young Adult

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-β (Aβ) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Animals; Brain; Cognitive Dysfunction; Gliosis; Male; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Neuroprotective Agents; Piperidines

Alzheimer's disease (AD) is an age-related neurodegenerative disease, and the imbalance between production and clearance of β-amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up-regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up-regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ-induced injury. The neuroprotection by thioperamide against AD was reversed by 3-MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic-related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic-lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB-dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy; Cell Death; Cell Survival; Cells, Cultured; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Hippocampus; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neurons; Neuroprotective Agents; Piperidines; Presenilin-1; Up-Regulation

Early Huntington's disease (HD) include over-activation of dopamine D

Topics: Animals; Cells, Cultured; Drug Delivery Systems; Female; Gene Knock-In Techniques; HEK293 Cells; Humans; Huntington Disease; Male; Mice; Mice, Transgenic; Piperidines; Receptors, Dopamine D1; Receptors, Histamine H3; Recombinant Fusion Proteins; Visual Cortex

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in

Topics: Animals; Biomarkers, Tumor; Cimetidine; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypersensitivity; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Mast Cells; Mice; Phosphoric Diester Hydrolases; Piperidines; Promethazine; Rabbits; Rats; Skin Diseases; Spider Venoms; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10 pg (44.2 fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a β2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles.

Topics: Animals; Anticonvulsants; Blood Flow Velocity; Butoxamine; Carnosine; Injections, Intramuscular; Kinetics; Male; Muscle, Skeletal; Physical Conditioning, Animal; Piperidines; Rats; Rats, Wistar; Sympathetic Nervous System; Sympatholytics; Synaptic Transmission

Unilateral labyrinthectomy (UL) causes the disappearance of ipsilateral medial vestibular nuclear (ipsi-MVe) activity and induces spontaneous nystagmus (SN), which disappears during the initial process of vestibular compensation (VC). Ipsi-MVe-activity restores in the late process of VC.. We evaluated the late process of VC after UL in rats and examined the effects of thioperamide (H3 antagonist) on VC.. MK801 (NMDA antagonist)-induced Fos-like immunoreactive (-LIR) neurons in contra-MVe, which had been suppressed by NMDA-mediated cerebellar inhibition in UL rats was used as an index.. The number of MK801-induced Fos-LIR neurons in contra-MVe gradually decreased to the same level as that of sham-operated rats 14 days after UL. Thioperamide moved the disappearance of the MK801-induced Fos-LIR neurons 2 days earlier. The number of MK801-induced Fos-LIR neurons in thioperamide-treated rats was significantly decreased, compared with that of vehicle rats on days 7 and 12 after UL. But, thioperamide did not influence the decline of SN frequency in UL rats.. These findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Biopsy, Needle; Disease Models, Animal; Functional Laterality; Immunohistochemistry; Male; Nystagmus, Pathologic; Otologic Surgical Procedures; Piperidines; Random Allocation; Rats; Rats, Wistar; Reference Values; Vestibular Function Tests; Vestibule, Labyrinth

Most cells acquire cholesterol by endocytosis of circulating low-density lipoproteins (LDLs). After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high-content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver of Npc1

Topics: Animals; Cells, Cultured; Cholesterol; Endosomes; Female; Fibroblasts; HeLa Cells; Humans; Lysophospholipids; Male; Mice; Mice, Inbred BALB C; Monoglycerides; Niemann-Pick Disease, Type C; Piperidines

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.

Topics: Animals; Anxiety; Arousal; Circadian Rhythm; Gamma Rhythm; Hippocampus; Histamine H3 Antagonists; Male; Mental Recall; Mice; Mice, Inbred C57BL; Parkinsonian Disorders; Piperidines; Recognition, Psychology

Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions. In the present work the action of a series of histamine receptors ligands on recombinant ASIC1a and ASIC2a was characterized. Two types of action were found for ASIC1a. 1-methylhistamine, N-alpha-methylhistamine, dimaprit and thioperamide caused significant potentiation, which was pH-dependent and voltage-independent. The H4R antagonist A943931 caused inhibition, which is likely due to voltage-dependent pore block. ASIC2a were virtually insensitive to the drugs tested. We conclude that ligands of histamine receptors should also be considered as ASIC modulators.

Topics: Acid Sensing Ion Channels; Animals; CHO Cells; Cricetulus; Dimaprit; Gene Expression Regulation; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Hydrogen-Ion Concentration; Ligands; Methylhistamines; Patch-Clamp Techniques; Piperidines; Receptors, Histamine; Recombinant Proteins; Signal Transduction

The aim of the current study was to investigate the interaction of the lipopolysaccharide (LPS) and histaminergic systems on appetite regulation in broilers. Effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptor antagonist), famotidine (histamine H2 receptor antagonist) and thioperamide (histamine H3 receptor antagonist) on LPS-induced hypophagia in broilers were studied. A total of 128 broilers were randomly allocated into 4 experiments (4 groups and 8 replications in each experiment). A cannula was surgically implanted into the lateral ventricle. In Experiment 1, broilers were ICV injected with LPS (20 ng) prior to α-FMH (250 nmol). In Experiment 2, chickens were ICV injected with LPS followed by chlorpheniramine (300 nmol). In Experiment 3, broilers were ICV injected with famotidine (82 nmol) after LPS (20 ng). In Experiment 4, ICV injection of LPS was followed by thioperamide (300 nmol). Then, cumulative food intake was recorded until 4 h post-injection. According to the results, LPS significantly decreased food intake. Chlorpheniramine significantly amplified food intake, and LPS-induced hypophagia was lessened by injection of chlorpheniramine. α-FMH, famotidine and thioperamide had no effect on LPS-induced hypophagia. These results suggest that there is an interaction between central LPS and the histaminergic system where LPS-induced hypophagia is mediated by H1 histamine receptors in 3 h food-deprived broilers.

Topics: Animals; Appetite Regulation; Chickens; Chlorpheniramine; Famotidine; Feeding Behavior; Food Deprivation; Histamine Antagonists; Infusions, Intraventricular; Lipopolysaccharides; Methylhistidines; Piperidines; Random Allocation

It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium.

Topics: Cell Adhesion; Cell Communication; Cell Line; Cell Separation; Cell Survival; Drug Inverse Agonism; Endothelium; Eosinophils; Histamine; Histamine Agonists; Histamine H1 Antagonists; Humans; Indoles; Ligands; Methylhistamines; N-Formylmethionine Leucyl-Phenylalanine; Piperazines; Piperidines; Receptors, Histamine

Myocardial infarction is an alarming health issue, needs great attention. The present study investigated the role of histamine-H3 receptor (H3R) agonist imetit in relationship to sympathetic and renin angiotensin system in Wistar rats.. Subcutaneous injection of isoproterenol (85 mg/kg) on last 2 consecutive days in per se group and 7 days treatment of different groups at 24 h interval induced myocardial infarction in Wistar rats. H3R agonist imetit (10 mg/kg), H3R antagonist thioperamide (5 mg/kg), losartan (10 mg/kg) were administered orally to evaluate imetit's cardioprotective potential effect by measuring plasma cardiac antioxidant markers, angiotensin II, norepinephrine levels and histopathological analysis.. Isoproterenol significantly elevated the angiotensin II and norepinephrine levels in rat plasma. This study revealed that pre-treatment with imetit similar to losartan attenuated norepinephrine and angiotensin II levels whereas thioperamide showed its antagonistic effect by diminishing imetit's effects. Furthermore, its protective effect was confirmed by restoration of cardiac antioxidant markers and histopathological improvement of myocardium integrity.. This study confirm imetit's cardioprotective potential and also reveals renin angiotensin system, sympathetic system and H3R correlation in isoproterenol induced toxicity in rats. However, molecular studies must be warranted to prove the role of H3R in myocardial infarction.

Topics: Angiotensin II; Animals; Antioxidants; Cardiotonic Agents; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Isoproterenol; Losartan; Male; Myocardial Infarction; Myocardium; Norepinephrine; Piperidines; Rats; Renin-Angiotensin System; Sympathetic Nervous System; Thiourea

Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine.. After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group.. Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect.. Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Carrageenan; Cetirizine; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists, Non-Sedating; Histamine H3 Antagonists; Imidazoles; Injections, Spinal; Joints; Male; Morphine; Osteoarthritis; Piperidines; Rats, Wistar; Receptors, Histamine H1; Receptors, Histamine H3; Spinal Cord

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100μM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.

Topics: Antipsychotic Agents; Apoptosis; Cell Differentiation; Clozapine; Granulocytes; Histamine Antagonists; HL-60 Cells; Humans; Methylhistamines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Tretinoin

Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1μg/mouse, i.c.v.) or histamine precursor, l-histidine (500, 1000mg/kg, i.p.) or low dose of histamine releasing agent (H3 receptor inverse agonist), thioperamide (2μg/mouse) attenuated the acute anitanxiety-like effect of ethanol (2g/kg, i.p, 8% w/v) in mice on EPM. However, pre-treatment with the H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50μg/mouse, i.c.v.) failed to affect the attenuating effect of low dose of histamine on ethanol induced anxiolysis. On the other hand, only H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) was able to partially reverse the attenuation of ethanol induced anxiolysis by l-histidine (1000mg/kg, i.p.). Surprisingly, in mice pre-treated with the higher dose of histamine (50μg/mouse, i.c.v.) or thioperamide (10μg/mouse, i.c.v.), the ethanol (2g/kg, i.p.) induced antianxiety-like effect was further enhanced on EPM. Furthermore, this potentiating effect of high dose of histamine on the ethanol (2g/kg, i.p.) was exacerbated on pre-treatment with the H1 receptor antagonist, cetirizine, while H2 receptor antagonist, ranitidine completely reversed this action of high dose of histamine on ethanol. Supportive to these results, i.c.v. pre-treatment with H1 receptor agonist, FMPH (2, 6.5μg/mouse, i.c.v.) attenuated while H2 receptor agonist, amthamine (0.1, 0.5μg/mouse, i.c.v.) enhanced the ethanol induced anxiolysis in mice. Thus, it is reasonable to contemplate that central histaminergic transmission functions to negatively modulate the acute ethanol-induced anxiolysis probably via stimulation of postsynaptic H1 receptor and histamine might contribute to the anxiolytic action of ethanol via H2 receptor activation.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Cetirizine; Ethanol; Histamine; Histamine H1 Antagonists; Histamine H3 Antagonists; Histidine; Male; Mice; Piperidines; Receptors, Histamine H1; Receptors, Histamine H3; Synaptic Transmission

Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin-angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus-a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system-in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague-Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats.

Topics: Acetylcholine; Animals; Blood Pressure; Chlorpheniramine; Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hemorrhage; Histamine; Histamine Agonists; Histamine Antagonists; Hypotension; Hypothalamus, Posterior; Male; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

This study has investigated whether pharmacological activation of Gi/o coupled histamine H3/H4 receptors inhibits the rat vasodepressor sensory outflow. For this purpose, 100 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with: 25mg/kg gallamine, 2mg/kg/min hexamethonium and 20μg/kg/min methoxamine, followed by i.v. continuous infusions of physiological saline (0.02ml/min) or immepip (3.1, 10 or 31μg/kg/min; a histamine H3/H4 receptor agonist). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V and 2ms) of the spinal cord (T9-T12) resulted in frequency-dependent vasodepressor responses, which were: (i) unchanged during the infusions of saline or immepip (3.1μg/kg/min); and (ii) significantly but, surprisingly, not dose-dependently inhibited by 10 and 31μg/kg/min immepip. Moreover, the sensory-inhibition by 10μg/kg/min immepip (which failed to inhibit the vasodepressor responses by i.v. bolus injections of α-CGRP; 0.1-1µg/kg) was: (i) essentially unaltered after i.v. administration of saline (1ml/kg) or blocking doses of the antagonists ketotifen (100μg/kg; H1), ranitidine (1000μg/kg; H2) or JNJ7777120 (310μg/kg; H4); and (ii) abolished after i.v. thioperamide (310µg/kg; H3). In conclusion, our results suggest that immepip-induced inhibition of the vasodepressor sensory outflow is mainly mediated by prejunctional activation of histamine H3 receptors.

Topics: Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Electric Stimulation; Heart Rate; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Piperidines; Rats; Receptors, Histamine H3; Spinal Cord

The antipsychotic properties of haloperidol are primarily attributed to its ability to block dopamine D2 receptors. Histaminergic transmission modulates some of the behavioral effects of haloperidol. Hence, the present study investigated the contribution of central histaminergic transmission in the cataleptic and neuroleptic effect of haloperidol respectively, using bar test and conditioned avoidance response (CAR) in a two-way shuttle box. The studies revealed that haloperidol (0.50 or 1 mg/kg, i.p.) exhibited cataleptic behavior and inhibited conditioned avoidance response (CAR) in the doses 0.25 or 0.50 mg in rats. The rats, pretreated centrally (i.c.v.) with histamine precursor, L-histidine (1, 2.5 μg) or histamine neuronal inducer (H3 receptor antagonist), thioperamide (20, 50 μg/rat), showed an enhanced cataleptic effect with sub-maximal dose of haloperidol (0.5 mg/kg, i.p.). Similarly, the neuroleptic effect of haloperidol (0.25 mg/kg, i.p.) in CAR was also potentiated in the rats pretreated with L-histidine (2.5 μg) or thioperamide (50 μg/rat). Further, the cataleptic effect of haloperidol (1 mg/kg, i.p.) was attenuated in rats pretreated with the H1 receptor antagonist, chlorpheniramine (60, 80 μg/rat, i.c.v.) or H2 receptor antagonist, ranitidine (60 μg/rat, i.c.v.). However, the neuroleptic effect of haloperidol (0.5 mg/kg, i.p.) was completely reversed by pretreatment with ranitidine (60 μg/rat, i.c.v.), and partially attenuated by chlorpheniramine (80 μg/rat, i.c.v.). These findings suggest the possible involvement of histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol probably via H1 or H2 receptor stimulation.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Catalepsy; Chlorpheniramine; Dose-Response Relationship, Drug; Drug Synergism; Haloperidol; Histamine; Histamine Agonists; Histidine; Infusions, Intraventricular; Male; Piperidines; Ranitidine; Rats; Receptors, Histamine; Synaptic Transmission

The aim of this study was to explain the involvement of the central histaminergic system in arachidonic acid (AA)-induced cardiovascular effects in normotensive rats using hemodynamic, immunohistochemistry, and microdialysis studies. Intracerebroventricularly (i.c.v.) administered AA (0.25, 0.5, and 1.0 μmol) induced dose- and time-dependent increases in mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. Central injection of AA (0.5 μmol) also increased posterior hypothalamic extracellular histamine levels and produced strong COX-1 but not COX-2 immunoreactivity in the posterior hypothalamus of rats. Moreover, the cardiovascular effects and COX-1 immunoreactivity in the posterior hypothalamus induced by AA (0.5 μmol; i.c.v.) were almost completely blocked by the H2 receptor antagonist ranitidine (50 and 100 nmol; i.c.v.) and partially blocked by the H1 receptor blocker chlorpheniramine (100 nmol; i.c.v.) and the H3-H4 receptor antagonist thioperamide (50 and 100 nmol; i.c.v.). In conclusion, these results indicate that centrally administered AA induces pressor and bradycardic responses in conscious rats. Moreover, we suggest that AA may activate histaminergic neurons and increase extracellular histamine levels, particularly in the posterior hypothalamus. Acting as a neurotransmitter, histamine is potentially involved in AA-induced cardiovascular effects under normotensive conditions.

Topics: Animals; Arachidonic Acid; Blood Pressure; Cardiovascular Physiological Phenomena; Chlorpheniramine; Cyclooxygenase 1; Cyclooxygenase 2; Heart Rate; Histamine; Histamine Antagonists; Hypothalamus, Posterior; Male; Neurons; Neurotransmitter Agents; Piperidines; Ranitidine; Rats, Sprague-Dawley

Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent were synthesized and tested for their ability to block neurodegenerative processes in vitro and in vivo. To identify a novel class of potential neuroprotective compounds, we prepared a series of bivalent ligands, in which a prototypic melatonergic ligand is connected to an imidazole-based H3 receptor antagonist through a flexible linker. Four imidazolyl-alkyloxy-anilinoethylamide derivatives, characterized by linkers of different length, were synthesized and their binding affinity for human MT1, MT2 and H3 receptor subtypes was evaluated. Among the tested compounds, 14c and 14d, bearing a pentyl and a hexyl linker, respectively, were able to bind to all receptor subtypes at micromolar concentrations and represent the first bivalent melatonergic/histaminergic ligands reported so far. These preliminary results, based on binding affinity evaluation, pave the way for the future development of new dual-acting compounds targeting both melatonin and histamine receptors, which could represent promising therapeutic agents for the treatment of neurodegenerative pathologies.

Topics: Binding Sites; Histamine Antagonists; Humans; Imidazoles; Ligands; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Structure, Tertiary; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptors, Histamine H3

Here, we have investigated whether learning and/or short-term memory was associated with release of ACh and glutamate in the rat nucleus accumbens (NAc). Additionally, neurotransmitter release in the NAc was assessed during facilitation of cognitive processes by antagonists of inhibitory histamine autoreceptors.. The olfactory, social memory test was used in combination with push-pull superfusion of the NAc. A male, juvenile rat was exposed twice to an adult male rat at intervals of 60 or 90 min, and release of ACh and glutamate was determined in the NAc of the conscious adult rat. Histamine receptor antagonists were applied i.c.v.. First exposure of a juvenile rat to an adult rat increased ACh and glutamate release in the NAc of the adult rat. Repetition of exposure after 60 min did not change release of ACh and glutamate, while contact time to recognition (CTR) was shortened. Repetition of exposure after an interval of 90 min prolonged CTR and enhanced accumbal ACh and glutamate release rates. Injection (i.c.v.) of thioperamide (histamine H3 receptor antagonist) together with famotidine (H₂ receptor antagonist), 80 min prior to second exposure, diminished CTR and abolished ACh and glutamate release when second exposure was carried out 90 min after the first one.. Histaminergic neurons per se facilitated short-term memory, without activation of cholinergic and/or glutamatergic neurons in the NAc of rats. Cholinergic and glutamatergic neurons within the NAc contributed to learning but not to recall of memory.

Topics: Acetylcholine; Animals; Famotidine; Glutamic Acid; Histamine; Histamine Antagonists; Learning; Male; Memory, Short-Term; Neurons; Nucleus Accumbens; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

Numerous studies have found that histamine plays a major role in memory and that the histamine H3 receptor (H3R) inverse agonist thioperamide improves cognitive performance in various animal models. However, little is known about the stages of memory that are specifically affected by thioperamide. The purpose of the present study was to investigate the effects of thioperamide on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in female C57BL/6J mice. In addition, potential state-dependency effects were studied by injecting thioperamide before the training and the test sessions in order to induce similar physiological states during acquisition and retrieval. Our results indicate that post-training systemic administration of thioperamide facilitated consolidation. Moreover, the administration of thioperamide before the training session had no effect on latency to enter the black compartment during training but enhanced memory during the retention test. The administration of thioperamide before the retention test also increased performance, which indicates that this compound ameliorates memory retrieval. Finally, when animals received thioperamide before the training session and before the retention test, the cognitive enhancing effects of thioperamide were not significantly changed. Together, our results show that thioperamide improves cognitive performance in an inhibitory avoidance task through actions on different memory stages. Furthermore, inducing a similar physiological state with thioperamide during acquisition and retrieval do not significantly affect cognitive enhancement. Our results suggest that the blockade of H3R can be helpful for the treatment of neuropsychiatric conditions characterized by deficits affecting several stages of memory processing.

Topics: Animals; Anxiety; Avoidance Learning; Brain Chemistry; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Female; Histamine; Histamine Agonists; Learning; Memory; Mice; Mice, Inbred C57BL; Motor Activity; Nootropic Agents; Piperidines; Psychomotor Performance

Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 μM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 μM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 μM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Corpus Striatum; Dopamine; Dopamine Agonists; Drug Interactions; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Male; Microdialysis; Microinjections; Piperidines; Rats; Receptors, Dopamine D1; Receptors, Histamine H3; Synaptic Transmission

The aim of this study was to identify the effects of 85% methanolic extract of Morus alba leaves (EMA), which is a traditional herb, in mice. The effects of EMA on the anxiolytic-like behaviour were studied using the elevated plus maze (EPM) and hole-board test. To elucidate the mode of action of the anxiolytic-like effects of EMA, the mice were subjected to the co-administration of EMA (200 mg/kg, per os (p.o.)) and either antagonist. EMA (at 200 or 400 mg/kg) significantly increased the percentages of time-spent in the open arms and entries into the open arms of the EPM versus vehicle-treated control group (p<0.05). Moreover, in the hole-board test, EMA (200 and 400 mg/kg) significantly increased the number of head-dips versus vehicle-treated control group (p<0.05). However, there were no changes in the locomotor activity and myorelaxant effects in any group compared with the vehicle-treated control group. In addition, the anxiolytic-like effects of EMA were abolished by thioperamide (10 mg/kg, intraperitoneally (i.p.)), which is a histamine H3 receptor antagonist. Moreover, results from reverse transcription polymerase chain reaction (RT-PCR) also revealed that the amygdalal histidine decarboxylase mRNA expression levels in EMA (200 mg/kg)-treated group were significantly higher than those in the vehicle-treated controls (p<0.05). These results suggest that EMA might prove to be an effective anxiolytic agent and that EMA acts via the histaminergic system in central nerve system.

Topics: Animals; Anti-Anxiety Agents; Behavior, Animal; Flumazenil; GABA-A Receptor Antagonists; Histamine H3 Antagonists; Histidine Decarboxylase; Male; Mice; Mice, Inbred ICR; Morus; Piperazines; Piperidines; Plant Extracts; Plant Leaves; Pyridines; Serotonin Antagonists

Recently we reported that cultured rat cortical astrocytes express histamine H3 receptor that is functionally coupled to Gi/o proteins and participates to the stimulatory effect of histamine. Due to the lack of data on the distribution of histamine H3 receptors on glial cells we further investigated their presence in cultured astrocytes from different brain regions. Real-time PCR was performed to examine the expression of native histamine H3 receptor in cultured rat astrocytes from cortex,cerebellum, hippocampus and striatum.Double-antigen immunofluorescence staining and[3H]N-α-methylhistamine([3H]NαMH) binding studies were utilized to specifically identify and characterize receptor binding sites in astrocytes. Histamine H3 receptor mRNA was detected in rat astrocytes from all the regions under investigation with the highest levels in striatal astrocytes followed by hippocampal astrocytes and approximately equal levels in cerebellar and cortical astrocytes.Double-antigen immunofluorescence confirmed the presence of histamine H3 receptors on the membrane of all examined astroglial populations.[3H]NαMH bound with high affinity and specificity to an apparently single class of saturable sites on cortical astrocytic membranes(KD¼4.5570.46 nM; Bmax¼5.6370.21 fmol/mg protein)and competition assays with selective agonists and antagonists were consistent with labeling of histamine H3 receptor(range of pKi values 7.50–8.87). Our study confirmed the ability of cultured astrocytes from different rat brain regions to express histamine H3 receptors.The observed diverse distribution of the receptors within various astrocytic populations possibly mirrors their heterogeneity in the brain and indicates their active involvement in histamine-mediated effects.

Topics: Animals; Animals, Newborn; Astrocytes; Binding, Competitive; Brain; Cells, Cultured; Ciprofloxacin; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; RNA, Messenger; Thiourea

Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol-induced behaviors. Part of this effect might be due to a modulation of ethanol-induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function.

Topics: Animals; Biphenyl Compounds; Brain; Ethanol; Female; Histidine; Hypnotics and Sedatives; Imidazoles; Mice; Nitriles; Piperidines; Pyrrolidines; Receptors, Histamine H3; Reflex, Righting; Thiourea

Histamine H(3) receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H(3) receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats.. Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus.. Intracerebroventricular (icv) injections with thioperamide (10 µg, 20 µg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide.. Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.

Topics: Animals; Anticonvulsants; Cyclic AMP Response Element-Binding Protein; Histamine H3 Antagonists; Kindling, Neurologic; Male; Memory Disorders; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Synaptic Transmission

The prevalence of allergic disease is increasing dramatically in the developed world. Studies of allergic diseases have clearly demonstrated that histamine plays an important role in the pathogenesis of the early-phase allergic response. Histamine effects are mediated by H1, H2, H3, and H4 receptors. The presence of the histamine H4 receptors on leukocytes and mast cells suggests that the new histamine receptor H4 plays an important role in the modulation of the immune system. Thus, histamine H4 receptor is an attractive target for anti-allergic therapy. In our present study, we have generated a histamine H4 receptor model using I-TASSER based on human B2-adrenergic G-protein-coupled receptor. Structurally similar compounds of the three known antagonists JNJ777120, thioperamide, and Vuf6002 were retrieved from PubChem, and database was prepared. Virtual screening of those databases was performed, and six compounds with high docking score were identified. Also the binding mode revealed that all the six compounds had interaction with Asp94 of the receptor. Our results serve as a starting point in the development of novel lead compounds in anti-allergic therapy.

Topics: Benzimidazoles; Binding Sites; Computational Biology; Drug Design; Histamine Antagonists; Humans; Indoles; Molecular Dynamics Simulation; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

Methamphetamine (MA) use increases the likelihood of engaging in risky sexual behavior and most MA-using women are of child-bearing age. Therefore, cognitive effects following MA exposure to the developing brain are concerning. Exposure of mice to MA during hippocampal development causes cognitive impairments in adulthood. These effects are more severe in female than male mice and mimicked by the H(3) receptor antagonist thioperamide (THIO). In this study, we assessed whether neonatal exposure to MA or THIO also affects cognition in adolescence. As these effects might be associated with alterations in circadian activity, we also assessed circadian activity in a subgroup of neonatally exposed mice. Sex-dependent treatment effects were seen in the water maze. While THIO-, but not MA-treated female mice showed hippocampus-dependent spatial memory retention in the first probe trial, MA-, but not THIO-treated female mice showed spatial memory retention in the probe trial following reversal training. In contrast, MA- and THIO-treated male mice showed spatial memory retention in both probe trials. When sensorimotor gating was assessed, MA-treated male mice showed greater pre-pulse inhibition than MA-treated female mice. Regardless of sex, THIO-treated mice gained on average more weight each day and showed an enhanced startle response. In addition, MA increased the length of the circadian period, with an intermediate effect following THIO treatment were observed. No treatment effects in exploratory behavior, measures of anxiety, or contextual or cued fear conditioning. Thus, the water maze is particularly sensitive to detect sex-dependent effects of neonatal MA and THIO exposure on spatial memory retention in adolescence.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Central Nervous System Stimulants; Circadian Rhythm; Conditioning, Psychological; Cues; Exploratory Behavior; Fear; Female; Functional Laterality; Histamine H3 Antagonists; Inhibition, Psychological; Male; Maze Learning; Methamphetamine; Mice; Mice, Inbred C57BL; Piperidines; Retention, Psychology; Sensory Gating; Sex Factors; Spatial Behavior

A metamorphic life-history is present in the majority of animal phyla. This developmental mode is particularly prominent among marine invertebrates with a bentho-planktonic life cycle, where a pelagic larval form transforms into a benthic adult. Metamorphic competence (the stage at which a larva is capable to undergo the metamorphic transformation and settlement) is an important adaptation both ecologically and physiologically. The competence period maintains the larval state until suitable settlement sites are encountered, at which point the larvae settle in response to settlement cues. The mechanistic basis for metamorphosis (the morphogenetic transition from a larva to a juvenile including settlement), i.e. the molecular and cellular processes underlying metamorphosis in marine invertebrate species, is poorly understood. Histamine (HA), a neurotransmitter used for various physiological and developmental functions among animals, has a critical role in sea urchin fertilization and in the induction of metamorphosis. Here we test the premise that HA functions as a developmental modulator of metamorphic competence in the sea urchin Strongylocentrotus purpuratus.. Our results provide strong evidence that HA leads to the acquisition of metamorphic competence in S. purpuratus larvae. Pharmacological analysis of several HA receptor antagonists and an inhibitor of HA synthesis indicates a function of HA in metamorphic competence as well as programmed cell death (PCD) during arm retraction. Furthermore we identified an extensive network of histaminergic neurons in pre-metamorphic and metamorphically competent larvae. Analysis of this network throughout larval development indicates that the maturation of specific neuronal clusters correlates with the acquisition of metamorphic competence. Moreover, histamine receptor antagonist treatment leads to the induction of caspase mediated apoptosis in competent larvae.. We conclude that HA is a modulator of metamorphic competence in S. purpuratus development and hypothesize that HA may have played an important role in the evolution of settlement strategies in echinoids. Our findings provide novel insights into the evolution of HA signalling and its function in one of the most important and widespread life history transitions in the animal kingdom--metamorphosis.

Topics: Animals; Apoptosis; Chlorpheniramine; Cimetidine; Ectoderm; Gene Expression Regulation, Developmental; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Histidine Decarboxylase; Larva; Metamorphosis, Biological; Methylhistidines; Organ Specificity; Piperidines; Receptors, Histamine H1; Strongylocentrotus purpuratus

Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H(3) receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H(4) receptor) to influence vestibular system function, using a selective H(4) receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584.. RT-PCR was used to assess the presence of H(4) receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H(4) receptor modulation in the rat vestibular system.. The transcripts of H(4) and H(3) receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H(4) receptor agonist 4-methylhistamine. Thioperamide, a H(3) /H(4) receptor antagonist, exerted effects similar to those of H(3) and H(4) receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H(4) receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects.. H(4) receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H(4) receptors as pharmacological targets for the treatment of vestibular disorders.

Topics: Animals; Benzimidazoles; Betahistine; Cells, Cultured; Female; Histamine Agonists; Histamine Antagonists; Histamine H3 Antagonists; Indoles; Neurons; Piperazines; Piperidines; Rats; Rats, Long-Evans; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Vestibular Nerve

Centrally acting histamine H(3) receptor ligands are proposed as potential treatments for obesity, although the value of inverse agonists at these receptors is still debated. Functional inhibition of H(3) autoreceptors activates neurones in a hypothalamic 'satiety' centre. The H(3) receptor antagonist, proxyfan was used as a tool to assess the action of histaminergic compounds in this model.. We compared the actions of histamine on feeding with those of an H(3) receptor agonist (imetit) and inverse agonist (thioperamide) in rats and mice. Sites of action were identified by immunohistochemistry and the hypothalamic ventromedial nucleus (VMN) was investigated using electrophysiological techniques.. Central histamine or thioperamide decreased fast-induced feeding, whereas imetit increased feeding. Systemic thioperamide entered the brain to activate hypothalamic feeding centres and to reduce feeding without causing any adverse behaviours. Thioperamide activated neurones in the VMN through an action on histamine autoreceptors, whilst imetit had the opposite effect. Proxyfan administered alone did not affect either feeding or electrical activity. However, it blocked the actions of both thioperamide and imetit, acting as a neutral antagonist in this system.. The H(3) receptor inverse agonist, thioperamide, potently reduced appetite without adverse behavioural effects. This action was blocked by proxyfan, acting as a neutral antagonist in this model and, therefore, this compound is useful in determining the selectivity of H(3) receptor-directed drugs. A major action of thioperamide is through presynaptic autoreceptors, inducing stimulation by endogenous histamine of postsynaptic H(1 ) receptors on anorectic hypothalamic neurones.

Topics: Animals; Eating; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Mice; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Thiourea; Ventromedial Hypothalamic Nucleus

As a first attempt at exploring an association between histaminergic and serotoninergic neuronal phenotypes in glucose regulation, the influence of the histamine H₃ receptor antagonist thioperamide on glucose uptake by brain was determined in rats in which the serotoninergic innervations of brain was largely destroyed perinatally. Male Wistar rats were initially treated on the 3rd day after birth with the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) (75 μg icv) or saline vehicle (10 μl icv). At 8 weeks lesioned and control rats were terminated in order to validate the effectiveness of 5,7-DHT: reduction in 5-HT and 5-HIAA by 83-91% and 69-83% in striatum, frontal cortex, and hippocampus (HPLC/ED method). Other groups of rats were pretreated with thioperamide (5.0 mg/kg ip) or saline vehicle 60 min prior to 6-[³H]-D-glucose (500 μCi/kg ip). Fifteen-min later rats were decapitated and brains were excised and dissected to remove frontal cortex, striatum, hippocampus, thalamus/hypothalamus, pons, and cerebellum. Liquid scintillation spectroscopy was used to determine that [³H]glucose uptake, which was enhanced in 5,7-DHT lesioned rats in cortex (by 88%), hippocampus, thalamus/hypothalamus, pons and cerebellum (each by 47-56%), and in striatum (by 35%). In contrast, thioperamide prevented the enhancement in [³H]glucose uptake in all brain regions of 5,7-DHT neonatally lesioned rats; and [³H]glucose levels were significantly different in all brain regions (except thalamus/hypothalamus) in thioperamide-versus saline-treated rats. These findings indicate a functional association between histaminergic and serotoninergic systems in brain in relation to glucose regulation.

Topics: 5,7-Dihydroxytryptamine; Animals; Animals, Newborn; Brain; Glucose; Histamine H3 Antagonists; Male; Piperidines; Radionuclide Imaging; Rats; Rats, Wistar; Serotonin; Tritium

We observed that olfactory stimulation with scent of grapefruit oil elevated the activities of sympathetic nerves, and increased the plasma glycerol concentration and blood pressure. In contrast, olfactory stimulation with scent of lavender oil had opposite effects in rats. These suggest that changes in autonomic activities cause physiological functions via histaminergic H1 and H3 receptor. Moreover, it has been reported that somatic sensory stimulation affected autonomic neurotransmission. To examine effects of skin application of urea-containing cream on cutaneous arterial sympathetic nerve activity (CASNA), blood flow, and transepidermal water loss (TEWL).. The activity of CASNA was determined by electrophysiological method, and cutaneous blood flow was determined using laser flowmeter in urethane-anesthetized rats, TEWL was measured using VapoMeter in the back skin of HWY hairless rats.. CASNA was markedly and significantly inhibited by skin application of 10% urea-containing cream, whereas cutaneous blood flow was significantly elevated via histaminergic H3-receptor. In conscious hairless rats, TEWL was significantly decreased 24 h after application of 10% urea-containing cream to the back skin.. These findings suggest that skin application of 10% urea-containing cream increases the cutaneous blood flow and water retaining ability, and that histaminergic H3-receptors may mediate these effects.

Topics: Administration, Topical; Anesthetics, Intravenous; Animals; Consciousness; Emollients; Histamine Antagonists; Male; Maleates; Piperidines; Rats; Rats, Hairless; Rats, Wistar; Receptors, Histamine H3; Regional Blood Flow; Skin; Sympathetic Nervous System; Urea; Urethane; Water

There is considerable interest in histamine H3 receptors as emerging pharmaceutical targets recently. Diabetic rats display increased pain responses following the injection of formalin into the paw suggesting the presence of hyperalgesia. In this study, the efficacy of systemic administration of selective H3 receptor agonist, immepip (1, 5 and 30 mg/kg), and antagonist, thioperamide (5, 15 and 30 mg/kg), was investigated on hyperalgesia during the formalin test in streptozocin (STZ)-induced diabetic rats. Nociceptive testing was performed in male adult Wistar rats 4 weeks after the onset of hyperglycemia. At the end of the experiment, all rats were weighed and then underwent plasma glucose measurement. Diabetes caused significant hyperalgesia during both phases of the formalin test. 5 and 30 mg/kg doses of immepip reversed chemical hyperalgesia in diabetic rats. The 1 mg dose of immepip did not alter pain behaviors in control and diabetic groups compared to the respective control ones. Immepip at any doses used in this study did not affect the body weight and plasma glucose levels of treated animals. Thioperamide alone at any doses used had no effect on formalin-induced nociceptive behaviors in the control and diabetic rats. The results indicated the efficacy of immepip systemic administration in an experimental model of diabetic hyperalgesia. It may also suggest it as a promising tool for treatment of painful diabetic neuropathy.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Histamine Agonists; Histamine H3 Antagonists; Hyperalgesia; Imidazoles; Male; Pain Measurement; Pain Threshold; Piperidines; Rats; Rats, Wistar

Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.

Topics: Animals; Diabetes Mellitus, Experimental; Histamine Agonists; Hypoglycemic Agents; Imidazoles; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

Sedating and non-sedating histamine H(1) receptor (H1R) antagonists and H2R blockers are widely used drugs which are generally considered to be safe medications. However, recently, these drugs have been shown to possibly impair the outcome of perforating appendicitis in children.. It was the aim of this study to characterize the effects of histamine receptor blockade in severe bacterial infections in more detail.. To obtain information on the safety of histamine receptor blockade in more detail, we used pharmacological and genetic approaches targeting histamine receptors and performed cecal ligation and puncture (CLP), a mouse model of septic peritonitis. After induction of septic peritonitis, morbidity and mortality were monitored closely.. Here, we show that oral treatment with first-generation H1R antihistamine diphenhydramine, H2R blocker cimetidine and H3/4R blocker thioperamide impairs optimal innate immune responses in severe murine bacterial sepsis. However, these adverse effects are not mediated by H1R, as mice deficient for H1R show similar rates of morbidity and mortality after CLP as their wild-type controls. Similarly, the second-generation antihistamine desloratadine neither affects morbidity nor mortality after CLP.. Our findings indicate that sedating first-generation H1R antihistamines and H2R blockers might impair innate immune responses to bacteria and that these drugs should be used with caution in patients with severe bacterial infections.

Topics: Animals; Anti-Allergic Agents; Bacterial Infections; Diphenhydramine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Histamine H3 Antagonists; Humans; Immunity, Innate; Loratadine; Mice; Mice, Inbred C57BL; Peritonitis; Piperidines; Receptors, Histamine; Sepsis

Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.

Topics: Animals; Dimaprit; Electric Stimulation; Electrochemistry; Histamine; Histamine Agonists; Histamine H3 Antagonists; Linear Models; Male; Medial Forebrain Bundle; Neural Pathways; Piperidines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Serotonin; Substantia Nigra

Functional roles of putative helix 8 in the carboxy-terminal tail of the human histamine H(3) receptor were investigated using deleted and alanine-substituted mutant receptors. While the deletion of the carboxy-terminal tail did not decrease the total expression level, surface expression, or ligand binding affinity, the agonist-stimulated cAMP response, [((35))S] GTPγS binding, and MAPK activation were totally abolished. The receptor lacking the carboxy-terminal tail also failed to respond to an inverse agonist, thioperamide, suggesting that the carboxy-terminal tail is involved in the regulation of receptor activity by changing G-protein coupling with the receptor. Site-directed mutagenesis revealed that hydrophobic amino acids in the putative helix 8 such as phenylalanines at position 419 (F7.60) and 423 (F7.64) or leucines at 426 (L7.67) and 427 (L7.68) were important for the agonist-induced activation of H(3) receptor. Substitution of F7.60 also resulted in a receptor that was less responsive to inactivation by the inverse agonist, implying the existence of an intermediate conformation that can be either activated or inactivated. Our results suggest that hydrophobic interface of putative helix 8 is important for the regulation of H(3) receptor activity, presumably by stabilizing the helix to the plasma membrane.

Topics: Amino Acid Sequence; Amino Acids; Cell Membrane; Cyclic AMP; Flow Cytometry; GTP-Binding Proteins; HEK293 Cells; Histamine; Histamine Agonists; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Piperidines; Plasmids; Protein Binding; Protein Structure, Secondary; Receptors, Histamine H3; Signal Transduction; Structure-Activity Relationship; Transfection

Albeit there is no doubt that histamine and its H(3) receptors participate in several aspects of learning and memory, such as memory consolidation, nothing is known about their potential involvement in memory reconsolidation. On the basis of previous reports of pro-cognitive effects of histamine H(3) receptor inverse agonists (which augment histamine release), we investigated to what extent the most representative of them, thioperamide, is able to facilitate reconsolidation of a contextually-conditioned fear memory in C57BL/6J mice. We also examined the effects of thioperamide on the stark disruptive effect that the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) typically exerts on both reconsolidation and consolidation. Post-training systemic injections (i.p.) of thioperamide facilitated consolidation at 10 and 20 mg/kg and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine at 5, 10 and 20 mg/kg. Importantly, none of the five thioperamide doses (2.5, 5, 10, 20 and 30 mg/kg) given right after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas all similarly given doses of dizocilpine (0.03, 0.06 and 0.12 mg/kg) disrupted it more or less equally. By contrast, thioperamide was able to unambiguously reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine at 10 and 20, but not 5 mg/kg. This is the first demonstration of an involvement of the interactive articulation between histamine and NMDA receptors in the mechanisms of memory reconsolidation, which seems to be indifferent to an increase of brain histamine per se. The results suggest a qualitatively different participation of histaminergic signalling in the mechanisms of reconsolidation and consolidation. The precise circuits within which these interactions take place are yet to be identified.

Topics: Analysis of Variance; Animals; Conditioning, Classical; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Electroshock; Excitatory Amino Acid Antagonists; Fear; Female; Freezing Reaction, Cataleptic; Histamine H3 Antagonists; Memory; Mice; Mice, Inbred C57BL; Piperidines

Information processing in the striatum is critical for basal ganglia function and strongly influenced by neuromodulators (e.g., dopamine). The striatum also receives modulatory afferents from the histaminergic neurons in the hypothalamus which exhibit a distinct diurnal rhythm with high activity during wakefulness, and little or no activity during sleep. In view of the fact that the striatum also expresses a high density of histamine receptors, we hypothesized that released histamine will affect striatal function. We studied the role of histamine on striatal microcircuit function by performing whole-cell patch-clamp recordings of neurochemically identified striatal neurons combined with electrical and optogenetic stimulation of striatal afferents in mouse brain slices. Bath applied histamine had many effects on striatal microcircuits. Histamine, acting at H(2) receptors, depolarized both the direct and indirect pathway medium spiny projection neurons (MSNs). Excitatory, glutamatergic input to both classes of MSNs from both the cortex and thalamus was negatively modulated by histamine acting at presynaptic H(3) receptors. The dynamics of thalamostriatal, but not corticostriatal, synapses were modulated by histamine leading to a facilitation of thalamic input. Furthermore, local inhibitory input to both classes of MSNs was negatively modulated by histamine. Subsequent dual whole-cell patch-clamp recordings of connected pairs of striatal neurons revealed that only lateral inhibition between MSNs is negatively modulated, whereas feedforward inhibition from fast-spiking GABAergic interneurons onto MSNs is unaffected by histamine. These findings suggest that the diurnal rhythm of histamine release entrains striatal function which, during wakefulness, is dominated by feedforward inhibition and a suppression of excitatory drive.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Channelrhodopsins; Corpus Striatum; Electric Stimulation; Excitatory Amino Acid Agents; Excitatory Postsynaptic Potentials; Feedback, Physiological; Female; GABA Agents; Green Fluorescent Proteins; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Transgenic; Mutation; Neural Inhibition; Neural Pathways; Neurons; Parvalbumins; Patch-Clamp Techniques; Piperidines; Receptors, Dopamine D1; Receptors, Dopamine D2; Synaptic Transmission; Thalamus; Transfection; Tyrosine 3-Monooxygenase; Vesicular Glutamate Transport Protein 1; Vesicular Inhibitory Amino Acid Transport Proteins

The current study aimed to investigate the effect of histamine-3 (H(3)) receptors, expressed in the tuberomammillary nucleus (TMN) of the hypothalamus and in the prefrontal cortex (PFC), on histamine neurotransmission in the rat brain. The firing activity of histamine neurons in the TMN was measured using in vivo extracellular single-unit electrophysiology, under propofol anesthesia. Extracellular histamine levels were determined using the dual (PFC and TMN) probe microdialysis, in freely-moving animals. Histamine levels in dialysates were determined using high-performance liquid chromatography (HPLC) and fluorescence detection. It was found that systemic administration of the selective H(3)-agonist, immepip, decreases, and the reverse H(3) /H(4)-agonist, thioperamide, increases the firing activity of histamine neurons in the TMN and the release of histamine in TMN and PFC. Local perfusion of immepip into the TMN increased, and thioperamide decreased, histamine levels in the TMN but not in the PFC. Local perfusion of immepip into the PFC, however, decreased extracellular histamine levels in both TMN and PFC. It can be concluded that brain H(3) receptors, and especially those expressed in the PFC, play an important role in the autoregulation of histamine neurotransmission. It is possible that H(3) receptors in the PFC are expressed on pyramidal neurons projecting to the TMN, and activation of these receptors diminishes glutamate excitatory input from PFC to the TMN. As the brain histamine system has a role in pathophysiology of psychotic, affective, cognitive, sleep and eating disorders, H(3) receptors are potential targets for future CNS medications.

Topics: Animals; Cerebral Cortex; Electrophysiology; Histamine; Histamine H3 Antagonists; Hypothalamus; Imidazoles; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Synaptic Transmission

Previous studies have demonstrated that central injection of L-carnosine (beta-alynyl-L-histidine), dipeptide synthesized in mammalian muscles, affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in anesthetized rats. In the present study, using urethane-anesthetized rats, we examined the dose-dependent effects of intravenous (IV) injection of various doses of anserine, dipeptide of similar structure to L-carnosine, on RSNA, BP and heart rate (HR). We found that injection of a low dose of anserine (1 microg) significantly suppressed RSNA, BP and HR. Conversely, a high dose (1000 microg) of anserine significantly elevated RSNA, BP and HR. Pretreatment with lateral cerebral ventricular (LCV) injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of anserine on RSNA, BP and HR. LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of anserine on RSNA, BP and HR. These findings suggest that anserine affects RSNA, BP and HR in a dose-dependent manner, and that the histaminergic nerve may be involved in the dose-different effects of anserine in rats.

Topics: Anesthetics, Intravenous; Animals; Anserine; Blood Pressure; Dipeptides; Diphenhydramine; Dose-Response Relationship, Drug; Heart; Histamine H1 Antagonists; Histamine H3 Antagonists; Injections, Intravenous; Kidney; Male; Piperidines; Rats; Rats, Wistar; Sympathetic Nervous System; Urethane

1. L-histidine is generally found in meat, poultry and fish. To investigate its effects on blood pressure, L-histidine was administered to 9-week-old spontaneously hypertensive rats (SHR). 2. Oral administration of L-histidine (100 mg / kg) increased histamine content in cerebrospinal fluid and reduced mean arterial pressure (MAP) in SHR. Intracerebroventricular injection of L-histidine (0.01 microg / 5 microL) also caused a decrease in MAP, which was reversed by cotreatment with the histamine H3 receptor antagonist thioperamide (20.4 microg / 5 microL, i.c.v.). There was a significant, time-dependent increase (over 6 h) in the NOx (NO2- + NO3-) content of the dialysate from the rostral ventrolateral medulla (RVLM), a major vasomotor centre, after oral administration of L-histidine. 3. In another experiment, SHR were treated with l-histidine (100 mg / kg) twice a day for 4 weeks. Chronic treatment with L-histidine inhibited the age-dependent increases in systolic blood pressure and urinary noradrenaline excretion seen in vehicle-treated SHR. Conversely, intracerebroventricular injection of thioperamide (20.4 microg / 5 microL, i.c.v.) reversed the decrease in MAP in response to L-histidine in SHR. 4. Reverse transcription-polymerase chain reaction analysis revealed that the aortic expression of angiotensin-converting enzyme mRNA was suppressed by chronic treatment with L-histidine. 5. These results suggest that L-histidine decreases blood pressure by attenuating sympathetic output via the central histamine H3 receptor in SHR. In addition, the antihypertensive effects of L-histidine appear to be associated with an increase in nitric oxide in the RVLM.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Injections, Intraventricular; Male; Medulla Oblongata; Nitric Oxide; Norepinephrine; Peptidyl-Dipeptidase A; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Histamine H3; Vasomotor System

G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low-frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions.

Topics: Amino Acid Sequence; Drug Discovery; Histamine H3 Antagonists; Humans; Imidazoles; Ligands; Models, Molecular; Molecular Sequence Data; Oximes; Piperidines; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Histamine H3; Sequence Alignment; Thiourea

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fentanyl; Freund's Adjuvant; Histamine Agonists; Hyperalgesia; Inflammation; Male; Methylhistamines; Mice; Naloxone; Pain; Piperidines; Receptors, Histamine H3; Skin; Substance P

Cholestasis is associated with changes including analgesia. The histaminergic system regulates pain perception. The involvement of histamine H(3) receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using immepip and thioperamide as selective H(3) receptor agonist and antagonist respectively. Cholestasis was induced by ligation of main bile duct using two ligatures and transsection the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatics. Administration of immepip (5 and 30mg/kg) and thioperamide (10 and 20mg/kg) to the cholestatic groups significantly increased and decreased TFLs compared to the saline treated cholestatic group. Immepip antinociception in cholestatic animals was attenuated by co-administration of naloxone. Immepip and thioperamide injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. The present data show that the histamine H(3) receptor system may be involved in the regulation of nociception during cholestasis in rats.

Topics: Animals; Behavior, Animal; Bile Ducts; Cholestasis; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Postural Balance; Rats; Rats, Wistar; Reaction Time; Receptors, Histamine H3

Cytochrome P450 46A1 (CYP46A1) initiates the major pathway of cholesterol elimination from the brain and thereby controls cholesterol turnover in this organ. We determined x-ray crystal structures of CYP46A1 in complex with four structurally distinct pharmaceuticals; antidepressant tranylcypromine (2.15 Å), anticonvulsant thioperamide (1.65 Å), antifungal voriconazole (2.35 Å), and antifungal clotrimazole (2.50 Å). All four drugs are nitrogen-containing compounds that have nanomolar affinity for CYP46A1 in vitro yet differ in size, shape, hydrophobicity, and type of the nitrogen ligand. Structures of the co-complexes demonstrate that each drug binds in a single orientation to the active site with tranylcypromine, thioperamide, and voriconazole coordinating the heme iron via their nitrogen atoms and clotrimazole being at a 4 Å distance from the heme iron. We show here that clotrimazole is also a substrate for CYP46A1. High affinity for CYP46A1 is determined by a set of specific interactions, some of which were further investigated by solution studies using structural analogs of the drugs and the T306A CYP46A1 mutant. Collectively, our results reveal how diverse inhibitors can be accommodated in the CYP46A1 active site and provide an explanation for the observed differences in the drug-induced spectral response. Co-complexes with tranylcypromine, thioperamide, and voriconazole represent the first structural characterization of the drug binding to a P450 enzyme.

Topics: Amino Acid Substitution; Anticonvulsants; Antidepressive Agents; Antifungal Agents; Brain; Catalytic Domain; Cholesterol; Cholesterol 24-Hydroxylase; Clotrimazole; Crystallography, X-Ray; Humans; Mutation, Missense; Piperidines; Protein Binding; Pyrimidines; Steroid Hydroxylases; Structure-Activity Relationship; Tranylcypromine; Triazoles; Voriconazole

Ligand pharmacology of histamine H(3)-receptors is species-dependent. In previous studies, two amino acids in transmembrane domain 3 (TM III) were shown to play a significant role. In this study, we characterized human and rat histamine H(3)-receptors (hH(3)R and rH(3)R, respectively), co-expressed with mammalian G proteins in Sf9 insect cell membranes. We compared a series of imidazole-containing H(3)R ligands in radioligand binding and steady-state GTPase assays. H(3)Rs similarly coupled to Gα(i/o)-proteins. Affinities and potencies of the agonists histamine, N(α)-methylhistamine and R-(α)-methylhistamine were in the same range. Imetit was only a partial agonist. The pharmacology of imetit and proxifan was similar at both species. However, impentamine was more potent and efficacious at rH(3)R. The inverse agonists ciproxifan and thioperamide showed higher potency but lower efficacy at rH(3)R. Clobenpropit was not species-selective. Strikingly, imoproxifan was almost full agonist at hH(3)R, but an inverse agonist at rH(3)R. Imoproxifan was docked into the binding pocket of inactive and active hH(3)R- and rH(3)R-models and molecular dynamic simulations were performed. Imoproxifan bound to hH(3)R and rH(3)R in E-configuration, which represents the trans-isomer of the oxime-moiety as determined in crystallization studies, and stabilized active hH(3)R-, but inactive rH(3)R-conformations. Large differences in electrostatic surfaces between TM III and TM V cause differential orientation of the oxime-moiety of imoproxifan, which then differently interacts with the rotamer toggle switch Trp(6.48) in TM VI. Collectively, the substantial species differences at H(3)Rs are explained at a molecular level by the use of novel H(3)R active-state models.

Topics: Animals; Blotting, Western; GTP Phosphohydrolases; Guanosine 5'-O-(3-Thiotriphosphate); Histamine; Humans; Imidazoles; Methylhistamines; Oximes; Piperidines; Rats; Receptors, Histamine H3; Species Specificity; Spodoptera

The present study was aimed to investigate the effects of microinjection of histamine, chlorpheniramine (a histamine H(1) receptor antagonist), ranitidine (a histamine H(2) receptor antagonist) and thioperamide (a histamine H(3) receptor antagonist) into the dentate gyrus on the formalin-induced pain. A biphasic pattern (first phase: 0-5min and second phase: 15-60min) in nociceptive responses was induced after subcutaneous injection of formalin (50μl, 2.5%) into the ventral surface of the right hind paw. Microinjection of histamine (1 and 2μg) into the dentate gyrus decreased the intensity of nociceptive responses. Intra-dentate gyrus microinjection of chlorpheniramine and ranitidine at the same doses of 1 and 4μg had no effects, whereas thioperamide at a dose of 4μg suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4μg prevented histamine (2μg)-induced antinociception, while thioperamide (4μg) increased histamine (2μg)-induced antinociception. These results indicated that activation of brain neuronal histamine at the levels of dentate gyrus produced antinociception. The post-synaptic H(1), H(2) receptors and pre-synaptic H(3) receptors of histamine may be involved in the histamine-induced antinociception at the level of the dentate gyrus.

Topics: Analgesics; Animals; Chlorpheniramine; Dentate Gyrus; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Male; Microinjections; Pain Measurement; Piperidines; Ranitidine; Rats; Rats, Wistar

Methionine-sulfoximine (MSO), a convulsant is known to increase the activity of histamine N-methyl transferase. The effect of a selective H3 receptor agonist R- (alpha) methylhistamine (RAMH) and antagonist (thioperamide, THP) and some antiepileptic drugs (gabapentin and sodium valproate) have been evaluated on MSO-induced convulsions in mice. The effect of THP was also evaluated in combination with these antiepileptic drugs. Sodium valproate (300 mg/kg, po) and gabapentin (400 mg/kg, po) offered protection against MSO-induced convulsions as evidenced by a significant prolongation of latency to abnormal dorsoflexion and complete protection against mortality within 6 h of administration. THP (15 mg/kg, ip) alone and in combination with sub-effective doses of gabapentin (75 mg/kg, po) and sodium valproate (75 mg/kg, po) revealed no significant differences from the control group or either drug alone. Hence, the convulsant action of MSO does not appear to be mediated via histaminergic mechanisms.

Topics: Amines; Animals; Anticonvulsants; Brain; Cyclohexanecarboxylic Acids; Drug Combinations; Gabapentin; gamma-Aminobutyric Acid; Male; Methionine Sulfoximine; Mice; Piperidines; Seizures; Valproic Acid

Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H3 receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice.. We investigated whether immepip, a selective H3 agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H3 inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide.. Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone.. The present results indicate that histamine released by thioperamide through the blockade of H3 autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H3 receptors located on non-histaminergic neurons.

Topics: Animals; Area Under Curve; Biphenyl Compounds; Cocaine; Dose-Response Relationship, Drug; Drug Interactions; Histamine; Histamine Agonists; Histamine Release; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nitriles; Piperidines; Pyrrolidines; Receptors, Histamine H3

Previous studies have demonstrated that neuromedin U (NMU) affects cardiovascular functions such as blood pressure (BP) or heart rate (HR) in rats. Here, we examined the effects of the lateral cerebral ventricular (ICV) injection of various doses of NMU on renal sympathetic nerve activity (RSNA) and BP in urethane-anesthetized rats. ICV injection of NMU elevated RSNA, BP and HR in a dose-dependent manner. Moreover, neither ICV pretreatment of thioperamide, an antagonist of histaminergic H3-receptor, or of diphenhydramine, an antagonist of histaminergic H1-receptor, abolished increasing effects of NMU on RSNA, BP and HR In addition, ICV injection of NMU suppressed gastric vagal nerve activity (GVNA) and activated brown adipose tissue sympathetic nerve activity (BAT-SNA) of anesthetized rats, and elevated brown adipose tissue temperature (BAT-T) of conscious rats. Thus, these evidence suggest that NMU affects neural activities of autonomic nerves containing RSNA, GVNA or BAT-SNA, and BP by mediating central mechanism.

Topics: Analysis of Variance; Animals; Autonomic Nervous System; Blood Pressure; Body Temperature; Cardiovascular System; Dose-Response Relationship, Drug; Heart Rate; Histamine H3 Antagonists; Injections, Intraventricular; Kidney; Male; Neuropeptides; Piperidines; Rats; Rats, Wistar; Telemetry; Time Factors

Previous studies have demonstrated that neuropeptide Y (NPY) affects blood pressure (BP) in anesthetized rats. Here, we examined the effects of the third cerebral ventricular (3CV) injection of various doses of NPY on renal sympathetic nerve activity (RSNA) and BP in anesthetized rats. 3CV injection of NPY suppressed RSNA and BP in a dose-dependent manner. Moreover, suppressing effects of NPY on RSNA and BP were eliminated by lateral cerebral ventricular (LCV) preinjection of thioperamide, an antagonist of histaminergic H3-receptor, not diphenhydramine, an antagonist of histaminergic H1-receptor. In addition, 3CV injection of NPY accelerated gastric vagal nerve activity (GVNA) and inhibited brown adipose tissue sympathetic nerve activity (BAT-SNA) of anesthetized rats, and lowered brown adipose tissue temperature (BAT-T) of conscious rats. Thus, these evidences suggest that central NPY affects autonomic nerves containing RSNA, GVNA or BAT-SNA, and BP by mediating central histaminergic H3-receptors.

Topics: Adipose Tissue, Brown; Adrenergic Fibers; Animals; Blood Pressure; Diphenhydramine; Dose-Response Relationship, Drug; Heart Rate; Histamine H1 Antagonists; Histamine H3 Antagonists; Injections, Intraventricular; Male; Neuropeptide Y; Piperidines; Rats; Rats, Wistar; Telemetry

In atopic dermatitis, inflammation induced by antigen-nonspecific stimuli further enhances the allergic inflammation. However, there is no experimental model in which allergic dermatitis is evoked where the inflammation has been induced by antigen-nonspecific stimuli. Here, we established a novel dermatitis model in mice and analyzed the role of histamine.. After sensitization with picryl chloride (PiCl) by painting on ear lobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting PiCl. Histamine antagonists and cyclosporine A (CsA) were administered intravenously.. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response, increased the infiltration of eosinophils and mast cells at the inflammatory site, shifted the cytokine milieu from Th1 to Th2 and induced the expression of thymic stromal lymphopoietin in the ear lobes. The PiCl-induced increase in the thickness of the ear lobe in the immediate phase was suppressed by the H1 antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H3/H4 antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on the TPA-modified contact dermatitis was as potent as that of CsA.. Induction of the antigen-nonspecific inflammation by TPA enhanced the PiCl-induced allergic inflammation. Histamine plays significant roles in the early-phase swelling via H1 receptors, and the late-phase swelling via H3/H4 receptors in this TPA-modified allergic dermatitis model.

Topics: Animals; Cell Count; Cimetidine; Cyclophosphamide; Cyclosporine; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Ear Auricle; Eosinophil Peroxidase; Eosinophils; Gene Expression; Histamine; Histamine Antagonists; Immunoglobulin E; Interferon-gamma; Interleukin-4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Picryl Chloride; Piperidines; Pyrilamine; Tetradecanoylphorbol Acetate; Thymic Stromal Lymphopoietin

The human histamine H(4)-receptor (hH(4)R) is expressed in mast cells and eosinophils and mediates histamine (HA)-induced chemotaxis via G(i)-proteins. For a detailed investigation of hH(4)R/G(i)-protein interaction, we coexpressed the hH(4)R with Galpha(i2) and Gbeta(1)gamma(2) as well as an hH(4)R-Galpha(i2) fusion protein with Gbeta(1)gamma(2) in Sf9 insect cells. The agonist radioligand [(3)H]HA showed a K(D) value of approximately 10 nM at hH(4)R and hH(4)R-Galpha(i2). The high-affinity states of hH(4)R and hH(4)R-Galpha(i2) were insensitive to guanosine 5'-[gamma-thio]triphosphate (GTPgammaS). The affinity of [(3)H]HA for hH(4)R was retained in the absence of mammalian G(i)-proteins. In steady-state GTPase- and [(35)S]GTPgammaS-binding assays, hH(4)R exhibited high constitutive activity and uncommon insensitivity to Na(+). Thioperamide (THIO) was only a partial inverse agonist. Addition of HA or THIO to baculovirus-infected (hH(4)R + Galpha(i2) + Gbeta(1)gamma(2)) Sf9 cells increased the B(max) in [(3)H]HA binding, but not in immunoblots, suggesting conformational instability and ligand-induced stabilization of membrane-integrated hH(4)R. No effect was observed on hH(4)R-Galpha(i2) expression, neither in [(3)H]HA binding nor in immunoblot. However, the expression level of hH(4)R-Galpha(i2) was consistently higher compared to hH(4)R, suggesting chaperone-like or stabilizing effects of Galpha(i2) on hH(4)R. In 37 degrees C stability assays, HA stabilized hH(4)R, and THIO even restored misfolded [(3)H]HA binding sites. Inhibition of hH(4)R glycosylation by tunicamycin reduced the [(3)H]HA binding B(max) value. In conclusion, (i) hH(4)R shows high constitutive activity and structural instability; (ii) hH(4)R shows a G-protein-independent high-affinity state; (iii) hH(4)R conformation is stabilized by agonists, inverse agonists and G-proteins; (iv) hH(4)R glycosylation is essential for cell-surface expression of intact hH(4)R.

Topics: Animals; Cell Line; Glycosylation; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Histamine; Humans; Immunoblotting; Insecta; Kinetics; Piperidines; Protein Stability; Radioligand Assay; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Recombinant Fusion Proteins; Sodium Chloride; Temperature; Tunicamycin

The aim of the present study was to determine the effect of the histaminergic precursor L-histidine and the H3 receptor antagonist thioperamide on the learning process of zebrafish submitted or not to confinement stress. On each of the 5 consecutive days of experiment (D1, D2, D3, D4, D5), animals had to associate an interruption of the aquarium air supply with food offering. Non-stressed zebrafish received an intraperitoneal injection of 100 mg/kg L-histidine, 10 mg/kg thioperamide or saline after training. Stressed animals received drug treatment and then were submitted to confinement stress for 1 h before the learning procedure. Time to approach the feeder was measured (in seconds) and was considered to be indicative of learning. A decrease in time to approach the feeder was observed in the saline-treated group (D1 = 141.92 +/- 13.57; D3 = 55 +/- 13.54), indicating learning. A delay in learning of stressed animals treated with saline was observed (D1 = 217.5 +/- 25.66). L-histidine facilitated learning in stressed (D1 = 118.68 +/- 13.9; D2 = 45.88 +/- 8.2) and non-stressed (D1 = 151.11 +/- 19.20; D5 = 62 +/- 14.68) animals. Thioperamide inhibited learning in non-stressed (D1 = 110.38 +/- 9.49; D4 = 58.79 +/- 16.83) and stressed animals (D1 = 167.3 +/- 26.39; D5 = 172.15 +/- 27.35). L-histidine prevented the increase in blood glucose after one session of confinement (L-histidine = 65.88 +/- 4.50; control = 53 +/- 3.50 mg/dL). These results suggest that the histaminergic system enhances learning and modulates stress responses in zebrafish.

Topics: Animals; Avoidance Learning; Blood Glucose; Dose-Response Relationship, Drug; Histamine H3 Antagonists; Histidine; Injections, Intraperitoneal; Piperidines; Stress, Physiological; Zebrafish

Topics: Animals; Aorta; Cimetidine; Ethylenediamines; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Male; Muscle Relaxation; Piperidines; Protein Isoforms; Rats; Rats, Wistar; Receptors, Histamine

Siberian hamsters develop hypophagia and increase catabolism of fat reserves in response to short photoperiods resulting in a natural loss of body weight in winter. We previously found that histamine 3 receptor (H3R) mRNA in the posterior hypothalamus is significantly decreased in short photoperiods. We hypothesized that this lower expression of H3R might contribute to the winter hypophagic state, therefore we examined the effects of the H3R agonist imetit and inverse agonists clobenpropit and thioperamide on food intake. We expressed the Siberian hamster H3R receptor in vitro and confirmed that imetit, clobenpropit and thioperamide are bound specifically, thus validating them as tools to investigate the role of H3R in vivo. Intracerebroventricular administration of histamine decreased food intake in hamsters in the fat summer state. Administration of imetit to hamsters in the lean state increased food intake, whereas administration of inverse agonists decreased food intake, though this was associated with decreased locomotor activity. Both H3R inverse agonists prevented the nocturnal rise in body temperature indicating additional effects on energy expenditure. In summary, our results suggest that increased availability of central histamine or the reduction of H3R activity decrease food intake. These effects are similar to those observed in hamsters in short photoperiods.

Topics: Animals; Body Temperature; Cell Line, Transformed; Cricetinae; Disease Models, Animal; Eating; Histamine; Imidazoles; Injections, Intraventricular; Motor Activity; Obesity; Phodopus; Photoperiod; Piperidines; Receptors, Histamine H3; Seasons; Thiourea; Transfection

Histamine 3 (H(3)) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H(3) receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H(3) receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.

Topics: Acetylcholine; Animals; Anticonvulsants; Brain; Cholinesterase Inhibitors; Cognition; Conditioning, Operant; Donepezil; Drinking Behavior; Drug Evaluation, Preclinical; Histamine Agonists; Histamine Antagonists; Imidazoles; Indans; Learning; Microdialysis; Morpholines; Muscarinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Scopolamine; Synaptic Transmission; Thiourea

Recent studies have raised the possibility that antagonists of H(3) histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia.. The purpose of this study was to determine if a prototypical H(3) antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia.. The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg).. Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment.. H(3) receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.

Topics: Animals; Dizocilpine Maleate; Drug Interactions; Histamine H3 Antagonists; Injections, Subcutaneous; Male; Memory; Motor Activity; Piperidines; Rats; Rats, Long-Evans; Reflex, Startle; Schizophrenia

Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 microl, i.t.) was significantly augmented in histamine H3 receptor knockout (-/-) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 microl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 microl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.

Topics: Analgesics, Opioid; Animals; Histamine Antagonists; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Pain; Pain Measurement; Pain Threshold; Piperidines; Receptors, Histamine H3; Time Factors

Histamine H3 receptors (H3R) are presynaptic heteroreceptors that negatively modulate the release of histamine and other neurotransmitters such as acetylcholine. Blocking H3 receptors with antagonists/inverse agonists has been shown to be procognitive and this effect has often been associated with increases in acetylcholine transmission. H3 receptors are abundantly expressed in the prefrontal cortex, an area associated with cognitive performance. While the procognitive effects of H3 receptor antagonists/inverse agonists may depend on alterations to acetylcholine or histamine release, other transmitters involved in cognitive processing such as glutamate and gamma-aminobutyric acid (GABA) may also be involved.. The purpose of the present study was to examine the effects of thioperamide, an H3 receptor antagonist, on extracellular levels of glutamate and GABA in the prefrontal cortex.. By means of in vivo microdialysis on freely moving Sprague Dawley rats, samples were collected and assayed via high-performance liquid chromatography coupled to electrochemical detection.. Replacement of calcium with magnesium revealed that the release of GABA, but not glutamate, was calcium-dependent. Thioperamide (10-20 mg/kg) did not affect basal glutamate or GABA release. Perfusion with a high concentration of potassium (100 mM) increased GABA, but not glutamate, release and thioperamide (20 mg/kg) attenuated the effects of high potassium on GABA release.. These data indicate that H3 receptors in the prefrontal cortex can enhance stimulated GABA release, but do not regulate basal levels of glutamate or GABA.

Topics: Animals; Chromatography, High Pressure Liquid; Extracellular Space; gamma-Aminobutyric Acid; Glutamic Acid; Histamine H3 Antagonists; Male; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley

Accumulated evidence suggests a role for histamine in cognition and the use of H3 receptor antagonists in the treatment of learning and memory disorders.. The aim of the current study was to investigate the cognition enhancing properties of ciproxifan, an H3 receptor antagonist, after natural forgetting in normal adult rats.. The novel object discrimination task, a recognition memory test based on spontaneous exploratory behaviour, was used. Briefly, rats exposed to two identical objects during an acquisition trial can discriminate between a novel object and a familiar one during a subsequent choice trial after a short delay but not after a 24-h inter-trial interval.. The scopolamine (0.5 mg/kg, i.p.)-induced impairment after a short delay was abolished by ciproxifan (p < 0.001). Natural forgetting was prevented by a single administration of ciproxifan (3 mg/kg) prior to the retention test (p < 0.001) but not when administered before or immediately after the acquisition trial (schedule effect p < 0.05), demonstrating a specific activity on memory retrieval. Pretreatment with either pyrilamine (10 mg/kg), an H1 antagonist, or zolantidine (10 mg/kg), an H2 antagonist, prevented the retrieval enhancement effect of ciproxifan (p < 0.05 and p < 0.001, respectively).. Histamine H3 receptor antagonists restore the performance of rats impaired by scopolamine and enhance recognition memory after acute administration before the retrieval phase via a mechanism dependent on H1 and H2 receptor activation.

Topics: Animals; Discrimination Learning; Discrimination, Psychological; Exploratory Behavior; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Histamine Release; Imidazoles; Male; Memory; Mental Recall; Muscarinic Antagonists; Piperidines; Psychomotor Performance; Rats; Rats, Wistar; Recognition, Psychology; Scopolamine

To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity several-fold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum--reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.

Topics: Age Factors; Animals; Animals, Newborn; Benzylamines; Brain; Chlorpheniramine; Cimetidine; Exploratory Behavior; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Male; Motor Activity; Norepinephrine; Piperidines; Rats; Rats, Wistar; Sympathomimetics

Histamine is an important chemical mediator of allergic rhinitis (AR). Histamine H(3) receptors (H(3)R) are located on cholinergic and NANC neurons of the myenteric plexus, and activation of H(3)R regulates gastric acid secretion. However, little is known about the localization and function of H(3)R in the upper airway.. The objective of this study was to examine the localization and possible function of H(3)R in the nasal mucosa.. We extracted total RNA from the inferior turbinate mucosa of patients with AR. H(3)R mRNA and beta-actin mRNA were amplified by RT-PCR. We used immunohistochemistry to examine localization of H(3)R protein in the inferior turbinate mucosa excised during clinically indicated surgery. We used alcian blue/periodic acid-shiff staining to examine the effects of the H(3)R agonist (R)-alpha-methylhistamine and the H(3)R antagonist thioperamide on secretion from rat submucosal glands.. H(3)R protein was expressed around submucosal gland cells. Thioperamide induced degranulation in the submucosal gland in the nasal septum.. The present results suggest that H(3)R is localized mainly around submucosal glands, and that H(3)R plays an important role in the secretion of submucosal glands in the nose.

Topics: Adolescent; Adult; Animals; Histamine H3 Antagonists; Humans; Immunohistochemistry; Male; Methylhistamines; Middle Aged; Nasal Mucosa; Piperidines; Rats; Rats, Inbred F344; Receptors, Histamine H3; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial; RNA, Messenger; Young Adult

The recently cloned histamine H(4) receptor is expressed predominantly in haematopoietic cells and has been found to modulate the function of mast cells, eosinophils, dendritic cells and T lymphocytes. It represents an attractive target for pharmacological interventions against a number of inflammatory and autoimmune disorders. In the present work we used two-electrode voltage-clamp to demonstrate histamine H(4) receptor modulation of G protein-coupled inward rectifier potassium (GIRK) channels heterologously expressed in Xenopus oocytes. In accordance with earlier findings in other effector systems, full agonism by histamine and (R)-alpha-methylhistamine, partial agonism by clobenpropit and inverse agonism by thioperamide were observed. Furthermore, in oocytes injected with low amounts of receptor cRNA, clobenpropit apparently acted as a neutral antagonist. We also used the high temporal resolution afforded by this system to study the differential time courses of response deactivation upon ligand washout for clobenpropit and (R)-alpha-methylhistamine. GIRK channels represent a novel effector system for histamine H(4) receptor modulation, which may be of physiological relevance and prove useful in the development of compounds targeting this receptor.

Topics: Animals; Electrophysiology; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; Methylhistamines; Oocytes; Patch-Clamp Techniques; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Thiourea; Xenopus

Previously, we showed that l-carnosine, a bioactive dipeptide, influences the sympathetic nerve activity innervating kidney and brown adipose tissue. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of L-carnosine on the sympathetic nerve activity innervating white adipose tissue (SNA-WAT) and lipolysis. We found that intraperitoneal (ip) administration of L-carnosine at doses of 100 ng/rat and 10 microg/rat elevated and suppressed SNA-WAT, respectively. The effect of lower dose of L-carnosine (100 ng/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of higher dose of L-carnosine (10 microg/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, ip administration of 100 ng and 10 microg of L-carnosine increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The changes of plasma FFAs resulting from the exposure to 100 ng and 10 microg of L-carnosine were diminished by the beta-adrenergic receptor blocker propranolol hydrochloride and the muscarinic receptor blocker atropine sulfate, respectively; and eliminated by the corresponding histamine receptor antagonists, which eliminated the changes in SNA-WAT. Our results suggest that low doses of L-carnosine may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. High doses of L-carnosine, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3) receptor, and the muscarinic receptor may be related to this response.

Topics: Adipose Tissue, White; Adrenergic beta-Antagonists; Animals; Atropine; Carnosine; Diphenhydramine; Dose-Response Relationship, Drug; Drug Interactions; Fatty Acids; Histamine H1 Antagonists; Histamine H3 Antagonists; Male; Muscarinic Antagonists; Piperidines; Propranolol; Rats; Rats, Wistar; Sympathetic Nervous System

Previously, we showed that orexin-A, a 33-aa peptide, influences renal sympathetic nerve activity. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of orexin-A on the sympathetic nerve activity innervating white adipose tissue (WAT-SNA) and lipolysis. We found that intracerebroventricular (icv) administration of orexin-A at doses of 1 microg/rat and 10 ng/rat elevated and suppressed WAT-SNA, respectively. The effect of the high dose of orexin-A (1 microg/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of the low dose of orexin-A (10 ng/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, icv administration of 1 microg/rat and 10 ng/rat of orexin-A increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The effect of 1 microg/rat of orexin-A on plasma FFA was eliminated by propranolol hydrochloride, a beta-adrenergic receptor blocker, and also by diphenhydramine. The effect of orexin-A at dose of 10 ng/rat disappeared by pretreatment with atropine sulfate, a muscarinic receptor blocker, and thioperamide maleate salt. Our results suggest that high doses of orexin-A may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. Low doses of orexin-A, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3)-receptor, and the muscarinic receptor may be related to this response.

Topics: Adipose Tissue, White; Adrenergic beta-3 Receptor Antagonists; Amino Acid Sequence; Animals; Atropine; Diphenhydramine; Histamine Antagonists; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins; Lipolysis; Male; Molecular Sequence Data; Muscarinic Antagonists; Neuropeptides; Orexins; Piperidines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Receptors, Histamine H1; Receptors, Histamine H3; Receptors, Muscarinic; Sympathetic Nervous System

With the rise in methamphetamine (MA) use among women of childbearing age, the potential consequences of MA exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these MA effects. Following MA administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic-pituitary-adrenal axis was activated. Co-administration of MA with the H3 receptor agonist immepip antagonized these effects. The effects of MA on histamine levels and on hypothalamic-pituitary-adrenal axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long-term cognitive effects of MA and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with MA or thioperamide showed reduced levels of the dendritic marker microtubule-associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and MA who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long-term effects of MA on cognitive function. These data support a role for histamine in the effects of MA on the developing brain.

Topics: Age Factors; Animals; Animals, Newborn; Brain; Central Nervous System Stimulants; Corticosterone; Enzyme-Linked Immunosorbent Assay; Female; Histamine; Histamine H3 Antagonists; Hypothalamo-Hypophyseal System; Imidazoles; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Piperidines; Pituitary-Adrenal System; Sex Factors; Time Factors

We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H(3)-receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg/kg, s.c.) with L-histidine (1000 mg/kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of L-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with L-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5 - 6 h after reperfusion. L-Histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.

Topics: Animals; Blood Cell Count; Body Water; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebral Cortex; Cytokines; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Microdialysis; Neostriatum; Piperidines; Rats; Rats, Wistar; Superoxide Dismutase

Histamine has been proposed to be an excitatory transmitter between the carotid body (CB) chemoreceptor (glomus) cells and petrosal ganglion (PG) neurons. The histamine biosynthetic pathway, its storage and release, as well as the presence of histamine H1, H2 and H3 receptors have been found in the CB. However, there is only indirect evidence showing the presence of histamine in glomus cells, or weather its application produces chemosensory excitation. Thus, we studied the histamine immunocytochemical localization in the cat CB, and the effects of histamine, and H1, H2 and H3 receptor blockers on carotid sinus nerve (CSN) discharge, using CB and PG preparations in vitro. We found histamine immunoreactivity in dense-cored vesicles of glomus cells. Histamine induced dose-dependent increases in CSN discharge in the CB, but not in the PG. The H1-antagonist pyrilamine reduced the CB responses induced by histamine, the H2-antagonists cimetidine and ranitidine had no effect, while the H3-antagonist thioperamide enhanced histamine-induced responses. Present data suggests that histamine plays an excitatory modulatory role in the generation of cat CB chemosensory activity.

Topics: Acetylcholine; Action Potentials; Animals; Carotid Body; Cats; Chemoreceptor Cells; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine H1 Antagonists; Histamine H3 Antagonists; Hypoxia; In Vitro Techniques; Male; Microscopy, Immunoelectron; Nicotine; Nicotinic Agonists; Piperidines; Pyrilamine; Tyrosine 3-Monooxygenase

In view of the recent evidence for the involvement of histamine in cerebral ischemia, the present study evaluated the effect of thioperamide (THP), a selective histamine H3-receptor antagonist, on middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. The rats were subjected to 2 h of MCAO followed by 22 h reperfusion after which the grip strength, locomotor activity and spontaneous alternation performance were assessed. Animals were then killed and oxidative stress markers were estimated in the whole brain. An elevation of thiobarbituric acid reactive substance (TBARS) and a reduction in glutathione (GSH) and antioxidant enzymes, such as glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), was observed following MCAO, the last two being statistically insignificant. Pretreatment with THP (5.5 mg/kg i.p. and 11 mg/kg i.p.) significantly reversed the MCAO-induced increase in TBARS, but could not reverse the other parameters. Paradoxically, it further reduced the levels of GPx, GR and SOD. No significant changes were observed in the catalase levels and in the grip strength and spontaneous alternation behavior of rats. Locomotor activity was reduced slightly, but reversed on pretreatment with THP. The dual effect of THP on oxidative stress requires further investigation and raises doubts on its possible use in cerebral ischemia.

Topics: Animals; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Histamine H3 Antagonists; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Maze Learning; Middle Cerebral Artery; Motor Activity; Muscle Strength; Oxidative Stress; Oxidoreductases; Piperidines; Rats; Rats, Wistar; Reperfusion Injury; Thiobarbituric Acid Reactive Substances

Preclinical findings demonstrate procognitive actions of histamine 3 (H3) receptor antagonists/inverse agonists. Since a prominent role of neuronal network oscillations of the hippocampus, such as theta band oscillation, has been recognized in numerous cognitive functions, in the present study, the potential involvement of H3 receptors in modulation of hippocampal theta activity has been investigated using various recording paradigms. Systemic administration of the selective H3 receptor antagonists/inverse agonists, thioperamide and ciproxifan (0.1 mg/kg to 1 mg/kg i.v.), dose dependently increased hippocampal theta power, similarly to methylphenidate (0.1-1 mg/kg i.v.), in chloral hydrate anesthetized rats. When hippocampal theta oscillation was elicited by electrical brainstem (nucleus pontis oralis) stimulation, ciproxifan (1 mg/kg i.v.) augmented the power of stimulation-induced theta. In contrast, systemic administration of methylphenidate (1 mg/kg i.v.) did not modify elicited theta. To analyze the role of H3 receptors on stage- and behavior-dependent hippocampal theta activity, polysomnographic recordings were carried out together with field potential recordings at the hippocampal fissure in freely moving rats for 8 h during the light phase of the circadian cycle. Systemic administration of ciproxifan (3.0 mg/kg, i.p.) promoted wakefulness with a concomitant reduction in cortical delta power and augmented novelty-induced hippocampal theta activity. These findings provide evidence that H3 receptors play an important role in regulation of hippocampal theta oscillation, representing one of the probable mechanisms involved in histamine-induced modulation of higher brain functions, such as attention and learning.

Topics: Anesthetics; Animals; Central Nervous System Stimulants; Chloral Hydrate; Electroencephalography; Electromyography; Hippocampus; Histamine H3 Antagonists; Imidazoles; Male; Methylphenidate; Muscle, Skeletal; Neck; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Theta Rhythm; Urethane

(1) The present study was designed to investigate whether histamine is involved in the protective effect of carnosine on Abeta42-induced impairment in differentiated PC12 cells. (2) PC12 cells were exposed to Abeta42 (5 muM) for 24 h after carnosine (5 mM) applied for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase inhibitor (alpha-fluoromethylhistidine) were added 15 min before carnosine. Cell viability, glutamate release or cell surface expression of NMDA receptor was examined. (3) Abeta42 caused a concentration-dependent reduction of viability in PC12 cells and pretreatment with carnosine ameliorated this impairment. This amelioration was reversed by the H(3) receptor antagonists thioperamide and clobenpropit, but not by either the H(1) receptor antagonist diphenhydramine or the H(2) receptor antagonist zolantidine. Further, alpha-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, also had no effect. In the presence of Abeta42, carnosine significantly decreased glutamate release and carnosine increased the surface expression of NMDA receptor. (4) These results indicate that the mechanism by which carnosine attenuates Abeta42-induced neurotoxicity is independent of the carnosine-histidine-histamine pathway, but may act through regulation of glutamate release and NMDA receptor trafficking.

Topics: Amyloid beta-Peptides; Animals; Benzothiazoles; Carnosine; Cell Differentiation; Diphenhydramine; Drug Interactions; Glutamic Acid; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Imidazoles; Neurons; Neurotoxins; PC12 Cells; Peptide Fragments; Phenoxypropanolamines; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Thiourea

Despite the well-established role of histamine as an anorexigenic neurotransmitter, the role of histamine H(3) receptors in feeding behavior is controversial. Herein we investigated the role of histamine H(3) receptor on several orexigenic agents in mice. Thioperamide (histamine H(3) receptor inverse agonist) inhibited neuropeptide Y- and nociceptin-induced hyperphagia but had no effect on U-50488 (opioid kappa-receptor agonist)-induced hyperphagia. In contrast, imetit (histamine H(3) receptor agonist) inhibited U-50488-induced hyperphagia but augmented neuropeptide Y-induced hyperphagia while it did not alter nociceptin-induced hyperphagia. These results indicate distinctive roles of histamine H(3) receptors in various orexigenic pathways.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Appetite; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Imidazoles; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Nociceptin; Opioid Peptides; Piperidines; Receptors, Histamine H3; Thiourea

Recent interests are beginning to be directed towards toxic neurobiological dysfunctions caused by lead (Pb) in aquatic vertebrates. In the present work, treatment with a maximum acceptable toxic concentration of this heavy metal was responsible for highly significant (p<0.01) abnormal motor behaviors such as hyperactive movements in the teleost Thalassoma pavo and the same treatment accounted for significantly (p<0.05) enhanced hyperventilating states. On the other hand, greater abnormal motor behaviors were detected in the presence of the histamine (HA) receptor subtype 2 (H(2)R) antagonist cimetidine (Cim), as shown by the very robust (p<0.001) increases of the two behavioral states. Interestingly, elevated expression levels of stress-related factors, i.e. heat shock protein70/90 (HSP90/70) orthologs were reported for the first time in hypothalamic and mesencephalic areas of Pb-treated teleosts. In particular, an up-regulation of HSP70 was readily detected when this heavy metal was given concomitantly with Cim, while the histamine subtype 3 antagonist (H(3)R) thioperamide (Thio), instead, blocked Pb-dependent up-regulatory trends of both chaperones in mostly hypothalamic areas. Moreover, intense neuronal damages of the above brain regions coincided with altered expressions of HSP70 and HSP90 when treated only with Cim. Overall these first results show that distinct H(n)R are able to exert a net neuroprotective role arising from their interaction with chaperones in fish exposed to Pb-dependent stressful conditions making this a potentially key interaction especially for T. pavo, aquatic species which plays an important ecological role towards the survival of other commercially vital fishes.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; Brain; Brain Chemistry; Cimetidine; Fishes; Fluoresceins; Fluorescent Dyes; Heat-Shock Proteins; Histamine H2 Antagonists; Histamine H3 Antagonists; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; In Situ Hybridization; Injections, Intraperitoneal; Lead Poisoning, Nervous System; Molecular Sequence Data; Organic Chemicals; Piperidines; Receptor Cross-Talk; Receptors, Histamine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.

Topics: Amphetamine; Animals; Benzhydryl Compounds; Brain; Central Nervous System Stimulants; Circadian Rhythm; Disorders of Excessive Somnolence; Food Deprivation; Histamine; Male; Modafinil; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Sleep; Sleep Deprivation; Synaptic Transmission; Wakefulness

Histamine is not only a crucial cytokine in the periphery but also an important neurotransmitter and neuromodulator in the brain. It is known to act on metabotropic H1-H4 receptors, but the existence of directly histamine-gated chloride channels in mammals has been suspected for many years. However, the molecular basis of such mammalian channels remained elusive, whereas in invertebrates, genes for histamine-gated channels have been already identified. In this report, we demonstrated that histamine can directly open vertebrate ion channels and identified beta subunits of GABA(A) receptors as potential candidates for histamine-gated channels. In Xenopus oocytes expressing homomultimeric beta channels, histamine evoked currents with an EC(50) of 212 microm (beta(2)) and 174 microm (beta(3)), whereas GABA is only a very weak partial agonist. We tested several known agonists and antagonists for the histamine-binding site of H1-H4 receptors and described for beta channels a unique pharmacological profile distinct from either of these receptors. In heteromultimeric channels composed of alpha(1)beta(2) or alpha(1)beta(2)gamma(2) subunits, we found that histamine is a modulator of the GABA response rather than an agonist as it potentiates GABA-evoked currents in a gamma(2) subunit-controlled manner. Despite the vast number of synthetic modulators of GABA(A) receptors widely used in medicine, which act on several distinct sites, only a few endogenous modulators have yet been identified. We show here for the first time that histamine modulates heteromultimeric GABA(A) receptors and may thus represent an endogenous ligand for an allosteric site.

Topics: Allosteric Site; Animals; Cell Line; Gene Expression Regulation; Histamine; Humans; Ion Channel Gating; Ligands; Models, Biological; Oocytes; Patch-Clamp Techniques; Piperidines; Rats; Receptors, GABA-A; Xenopus laevis

Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control. We demonstrate a significant interaction of olanzapine treatment with histamine neurotransmission in a rat-feeding paradigm measuring the consumption of a palatable fat emulsion. This interaction was identified using the H3 receptor antagonist thioperamide, which by blocking autoreceptor control of histaminergic neurons enhances release of hypothalamic histamine, causing hypophagia. We challenged this effect of thioperamide with olanzapine, which among its pharmacological actions is a potent H1 receptor antagonist. Olanzapine pretreatment significantly attenuated thioperamide-induced hypophagia. Pretreatment of thioperamide with ziprasidone, an AAPD with negligible H1 receptor affinity, however, failed to have this effect. Although thioperamide may also increase levels of neurotransmitters other than histamine, the potent H1 antagonist property of olanzapine is likely to result in the suppression of thioperamide-induced hypophagia. We conclude that olanzapine may be directly modulating histaminergic neurotransmission associated with the regulation of feeding behaviour.

Topics: Animals; Antipsychotic Agents; Appetite; Benzodiazepines; Brain; Dose-Response Relationship, Drug; Eating; Fat Emulsions, Intravenous; Histamine; Histamine H1 Antagonists; Histamine H3 Antagonists; Hypothalamus; Male; Neurons; Olanzapine; Piperazines; Piperidines; Rats; Synaptic Transmission; Taste; Thiazoles

Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of L-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of L-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery (n=18), surgical brain injury without treatment (SBI) (n=33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI+H) (n=29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. L-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI+H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood-brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI+H groups, similar histological outcomes between SBI and SBI+H, and similar qualitative staining for cleaved caspase 3. SBI+H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.

Topics: Animals; Apoptosis; Blood-Brain Barrier; Body Water; Brain Chemistry; Brain Injuries; Coloring Agents; Evans Blue; Functional Laterality; Histamine; Histamine Antagonists; Histidine; Immunohistochemistry; Male; Mice; Neurosurgical Procedures; Physical Stimulation; Piperidines; Postoperative Complications; Vibrissae; Walking

As prenatal methamphetamine (MA) exposure results in long-term hippocampus-dependent cognitive deficits, the increased MA use in women of childbearing age is of great concern. As mice are most commonly used in genetic models, we started to study the potential effects of neonatal MA exposure in female and male mice on brain function 3 months later. As histamine (HA) might mediate some effects of MA in adulthood, we also tested whether in neonates HA might mediate the long-term effects of MA using HA H(3) receptor agonists and antagonists. Stimulation of HA H(3) receptors by H(3) agonists inhibits HA synthesis and release, whereas inhibition of H(3) receptors by H(3) receptor antagonists increases HA release. MA (5 mg/kg), the H(3) receptor antagonist thioperamide (5 mg/kg), and the H(3) receptor agonist immepip (5 mg/kg) alone or in the presence of MA (5 mg/kg) were administered once daily from postnatal days 11 to 20 and the mice were tested at 3 months of age. Here we show that in mice exposure to MA early in life causes sex-dependent impairments in object recognition, spatial learning, and memory in the water maze, and pre-pulse inhibition in adulthood. HA mediates these impairments. Increasing HA release mimicked, whereas inhibiting HA release blocked the long-term detrimental MA effects. This model could be used to determine the role of genetic and environmental factors in MA-dependent cognitive impairments and to develop therapeutic strategies to inhibit them.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Cognition; Dopamine Uptake Inhibitors; Exploratory Behavior; Histamine; Histamine Antagonists; Imidazoles; Inhibition, Psychological; Maze Learning; Methamphetamine; Mice; Mice, Inbred C57BL; Piperidines; Reflex, Startle; Rotarod Performance Test; Sex Characteristics; Spatial Behavior

Intracellular calcium regulation is vital for cells, especially for neurons; raised levels are associated with cytotoxicity and neuronal death. In this report, we present the first experimental evidence showing a concentration-dependent reduction of free calcium in the mouse brain synaptosomes by thioperamide (THP), an H3 receptor antagonist. This is interesting in view of the recent reports on the anticonvulsant and cognition facilitating effects of THP. A neuroprotective potential of THP is suggested.

Topics: Analysis of Variance; Animals; Brain; Calcium; Dose-Response Relationship, Drug; Extracellular Fluid; Histamine Antagonists; Mice; Piperidines; Synaptosomes

Since the histidine-containing dipeptide carnosine (beta-alanyl-L-histidine) is believed to have many physiological functions in the brain, we investigated the neuroprotective effects of carnosine and its mechanisms of action in an in vitro model of neurotoxicity induced by N-methyl-d-aspartate (NMDA) in differentiated PC12 cells. Pretreatment with carnosine increased the viability and decreased the number of apoptotic and necrotic cells measured by MTT and Hoechst 33342 and propidium iodide (PI) double staining assays. Carnosine also can inhibit the glutamate release and increase HDC activity and the intracellular and extracellular contents of carnosine, histidine and histamine detected by high-performance liquid chromatography (HPLC). The protection by carnosine was reversed by alpha- fluoromethylhistidine, a selective and irreversible inhibitor of histidine decarboxylase (HDC). Pyrilamine and thioperamide, selective central histamine H(1) and H(3) antagonists also significantly reversed the protection of carnosine. Further, the inhibition of glutamate release by carnosine was reversed by thioperamide. Therefore, the protective mechanism of carnosine may not only involve the carnosine-histidine-histamine pathway, but also H(1)/H(3) receptors and the effective inhibition of glutamate release. This study indicates that carnosine may be an endogenous protective factor and calls for its further study as a new antiexcitotoxic agent.

Topics: Animals; Carnosine; Cell Differentiation; gamma-Aminobutyric Acid; Glutamic Acid; Histamine; Histidine; Methylhistidines; N-Methylaspartate; Neurons; PC12 Cells; Piperidines; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

Inflammation is a crucial factor in the development of ischemia-induced brain injury. Since facilitation of central histaminergic activity ameliorates reperfusion injury, effects of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with antibodies against myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12-24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by L-histidine injections. The L-histidine administration decreased the number of CD4+ T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of thioperamide prolonged the effect. Although administration of mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration, ranitidine tended to reverse the effect of L-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through histamine H2 receptors, which may be a mechanism underlying the protective effect of L-histidine.

Topics: Animals; Antigens, CD; Brain Ischemia; CD4-Positive T-Lymphocytes; Cell Count; Drug Combinations; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine; Immunohistochemistry; Infarction, Middle Cerebral Artery; Male; Neutrophils; Peroxidase; Piperidines; Pyrilamine; Random Allocation; Ranitidine; Rats; Rats, Wistar; Receptors, Histamine; Reperfusion; Time Factors

Unilateral lesion of the vestibular system induces posturo-locomotor deficits that are compensated for with time. Drug therapy is currently used to improve the recovery process and to facilitate vestibular compensation. We investigated the effects of thioperamide on functional recovery after unilateral labyrinthectomy in Carassius auratus. Approximately 24h after surgery, the animals were injected intraperitoneally with thioperamide (15 mg/kg) and saline (1.5 ml/kg). The injections were repeated daily for a total of 15 consecutive days. The substances were administered in a volume of 1.5 ml/kg body weight. Another group, which served as a non-lesion control, did not receive unilateral labyrinthectomy or system injections. Animals treated with saline presented a compensatory decrease in body tilt on the 7th day, while the animals treated with thioperamide presented a decrease in body tilt from the 13th day, suggesting a delay in the functional recovery process. These results suggest that an increase in cerebral histamine levels impairs vestibular compensation in goldfish.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Behavior, Animal; Functional Laterality; Goldfish; Histamine Antagonists; Labyrinth Diseases; Nystagmus, Pathologic; Piperidines

Neuronal histamine regulates several functions in the vertebrate brain. The zebrafish brain contains a widespread histaminergic system and H(3) receptor ligand binding has been reported. In this study we provide evidence for the existence of histamine H(1), H(2) and H(3) receptor genes in zebrafish. Single copies of putative histamine H(1), H(2) and H(3) receptors were identified and cloned from the zebrafish brain. Expression analysis suggested that they are expressed in the brain and a few other tissues. Widespread distribution of zebrafish H(2) receptor binding sites was detected with [(125)I]iodoaminopotentidine in brain sections. Zebrafish larvae were exposed to 1, 10 or 100 microM of the H(1) ligand pyrilamine, the H(2) ligand cimetidine and the H(3) ligands thioperamide and immepip for 5 days. Significant decreases in swimming distance were observed with the highest dose of all ligands, whereas cimetidine gave a significant decrease also with 1 and 10 microM doses. These results provide the first molecular biological evidence for the presence of histamine receptors in zebrafish. These histamine receptors resemble those of higher vertebrates and they provide a useful model for pharmacological and behavioral studies for characterizing the functions of histamine in more detail.

Topics: Animals; Behavior, Animal; Cimetidine; Histamine Agonists; Histamine Antagonists; Imidazoles; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Zebrafish

Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Galpha(i/o) proteins reducing adenosine 3', 5'-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

Topics: Animals; Bile Ducts; Bile Ducts, Intrahepatic; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Gene Expression Regulation, Enzymologic; Histamine; Histamine Agonists; Hyperplasia; Ligation; Liver; Male; MAP Kinase Signaling System; Methylhistamines; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Protein Serine-Threonine Kinases; Rats; Rats, Inbred F344; Receptor, EphA8; Receptors, Histamine H3

The central histaminergic system is reported to mediate behavioural, hormonal and physiological homeostasis of living organisms. Recent reports indicate its prominent role in various neurobehavioural disorders such as depression and psychosis. This study evaluated the effect of activation of the central histaminergic system in anxiety-like conditions, using the elevated plus-maze test in mice, and elucidated the role of different histaminergic receptors mediating such effects. Peripheral administration of L-histidine (L-His), in a dose-dependent manner, significantly decreased the exploration time in open arms and number of entries into open arms without modifying the number of entries into closed arms of the elevated plus-maze, indicating anxiogenesis. Further, such effects of central histamine were significantly attenuated, in a dose-dependent manner, by pretreatment with pyrilamine (H1 receptor antagonist). Pretreatment with either zolantidine (H2 receptor antagonist) or thioperamide (H3 receptor antagonist), however, failed to attenuate the L-His-induced anxiogenesis. Our results indicate that anxiogenic effects of central histaminergic system appear to be mediated prominently by activation of H1 receptors.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Benzothiazoles; Diazepam; Dose-Response Relationship, Drug; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine; Male; Mice; Phenoxypropanolamines; Piperidines; Pyrilamine; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H3

Nicotinic systems have been found in a variety of studies to play important roles in cognitive function. Nicotinic involvement in different aspects of cognitive function such as learning vs. memory may differ. We have found in rats that the spatial repeated acquisition task in the radial-arm maze is significantly improved by low doses of the nicotinic receptor antagonist mecamylamine, the atypical nicotinic receptor ligand lobeline, as well as the alpha7 nicotinic receptor agonist ARR-17779. Interestingly, nicotine in the same dose range that improves working memory in the win-shift radial maze task was not effective in improving repeated acquisition performance. Nicotinic systems interact with a variety of other neural systems. Differential involvement of these extended effects with learning vs. memory may help explain differential effects of nicotinic drugs with these cognitive functions. Histamine H(3) receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found impairment. Nicotine stimulates the release of histamine. This effect may counter other cascading effects of nicotine in the performance of learning and memory tasks. A specific test of this hypothesis involves our study of nicotine (0.1-0.4 mg/kg) interactions with the histamine H(3) receptor antagonist thioperamide (2.5-10 mg/kg) on learning memory in the repeated acquisition test in the radial-arm maze. The highest dose of thioperamide tested caused a significant choice accuracy impairment, which was most evident during the later portions of the learning curve. The highest dose of nicotine did not change overall errors but did cause a significant impairment in learning over trials. The choice accuracy impairment induced by thioperamide was significantly attenuated by nicotine (0.4 mg/kg). The learning impairment caused by the highest dose of nicotine was significantly attenuated by thioperamide. Thioperamide also caused a slowing of response, an effect, which was attenuated by nicotine co-administration. The repeated acquisition test can help differentiate acute drug effects on learning. Nicotine and thioperamide effectively reversed each other's choice accuracy impairment even though each by itself impaired accuracy.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Anticonvulsants; Behavior, Animal; Dose-Response Relationship, Drug; Female; Histamine Antagonists; Injections, Subcutaneous; Maze Learning; Nicotine; Nicotinic Agonists; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor Cross-Talk; Receptors, Histamine H3; Receptors, Nicotinic; Reinforcement, Psychology

This study analysed the effects of betahistine and thioperamide, two histamine H(3) receptor antagonists, on the recovery process after unilateral vestibular neurectomy (UVN) in the cat. In UVN animals untreated or treated with betahistine or thioperamide, recovery was evaluated by recording the horizontal spontaneous nystagmus and the postural and locomotor performances. The neurochemical effects of these drugs were determined by examining their impact on the histaminergic system. We quantified the mRNA coding for histidine decarboxylase (enzyme synthesizing histamine) by in situ hybridisation in the tuberomammillary nuclei, while binding density to histamine H(3) receptors was assessed using a histamine H(3) receptor agonist ([(3)H]N-alpha-methylhistamine) and autoradiography methods in the tuberomammillary and the vestibular nuclei. Relative to the UVN-untreated group, cats treated with betahistine or thioperamide showed strongly accelerated behavioural recovery. UVN-induced 1) an up-regulation of histidine decarboxylase mRNA in the tuberomammillary nuclei, strongly accentuated under betahistine and thioperamide, 2) a reduction of the binding to histamine H(3) receptors in the vestibular and tuberomammillary nuclei, also strongly enhanced in both groups of treated cats. This study demonstrates that betahistine and thioperamide strongly improve the recovery of vestibular functions in UVN cats by interacting with the histaminergic system.

Topics: Animals; Behavior, Animal; Betahistine; Cats; Histamine Agonists; Histamine Antagonists; Histidine Decarboxylase; Ligands; Methylhistamines; Nystagmus, Pathologic; Piperidines; Postural Balance; Receptors, Histamine H3; RNA, Messenger; Vestibular Nerve; Vestibular Nuclei

The histamine H(3) receptor is a constitutively active G protein-coupled receptor for the neurotransmitter histamine that serves a negative feedback function. A role for the histamine H(3) receptor has been suggested in neurodegenerative diseases, such as Parkinsons disease and Alzheimer's disease. Mice deficient in apolipoprotein E (apoE), a protein involved in development, regeneration, neurite outgrowth, and neuroprotection, show increased measures of anxiety and reduced sensitivity to effects of histamine H(3) receptor antagonists on measures of anxiety. In this study, we tested whether in mice lacking apoE (Apoe-/-) histamine levels and histamine release in brain areas involved in the regulation of anxiety are altered. H(3) receptor antagonist-induced histamine release was lower in the amygdala of Apoe-/- than wild-type mice. In contrast, there were no genotype differences in histamine release in the hypothalamus. Consistent with these data, histamine immunohistochemistry revealed lower total and synaptic histamine levels in the central nucleus of the amygdala of Apoe-/- than wild-type mice. Such changes were not seen in the hypothalamus, hippocampus, or cortex. In Apoe-/- mice, chronically decreased histamine levels and reduced histamine release in the amygdala might contribute to increased measures of anxiety.

Topics: Amygdala; Animals; Anxiety; Apolipoproteins E; Cerebral Cortex; Hippocampus; Histamine; Histamine Antagonists; Hypothalamus; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Piperidines; Receptors, Histamine H3; Synapses

Pharmacological activation of histamine H3 receptors is known to reduce the release of inflammatory peptides, thereby reducing pain and inflammation, but the site(s) and mechanism(s) of these effects are currently unknown. The present study addressed these questions by examining the effects of the H3 agonist immepip and the H3 antagonist thioperamide on nociceptive behaviors and swelling produced during the rat formalin test. Systemic administration of immepip (5 and 30 mg/kg, s.c.) significantly attenuated formalin-induced flinching but not licking responses during both phases. This attenuation was reversed by either systemic (15 mg/kg, i.p.) or intrathecal (20 or 50 microg) administration of thioperamide. Furthermore, immepip (30 mg/kg, s.c.) significantly inhibited formalin-induced swelling, an action which was completely reversed by systemic (15 mg/kg, i.p.), but not intrathecal (50 microg) thioperamide. Also consistent with this pattern, intrathecal immepip (50 microg) reduced flinching responses, but had no effect on formalin-induced paw swelling. The present findings suggest that activation of H3 receptors located on peripheral and spinal terminals of deep dermal fibers attenuates formalin-induced swelling and flinching, respectively. Pharmacological stimulation of H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory pain.

Topics: Animals; Behavior, Animal; Brain; Edema; Formaldehyde; Histamine Agonists; Histamine Antagonists; Imidazoles; Inflammation; Injections, Spinal; Male; Nerve Endings; Nerve Fibers; Neurons, Afferent; Pain Measurement; Peripheral Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Skin; Spinal Cord

Topics: Animals; Blood Circulation; Colitis; Histamine Antagonists; Piperidines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Regional Blood Flow; Trinitrobenzenesulfonic Acid

We describe here the protein expression of H4 histamine receptor in cells of the innate immune system, which include NK cells, monocytes, and dendritic cells (DCs). Anti-H4R specifically stained permeabilized NK cells, THP-1 clone 15 monocytes, and DCs. This binding was inhibited by incubating anti-H4R Ab with its corresponding peptide. Histamine induced NK cells, THP-1 clone 15 cells, and DCs chemotaxis with high affinity. The ED(50) chemotactic effect was 5 nM, 6.8 nM, and 2.7 nM for NK cells, THP-1 clone 15 cells, and DCs, respectively. Thioperamide, an H3R/H4R antagonist, inhibited histamine-induced chemotaxis in all these cells. However, histamine failed to induce the mobilization of [Ca(2+)](i) in NK cells and THP-1 clone 15 cells, but it induced calcium fluxes in DCs. Using a new method of detecting NK cell-mediated cytolysis, it was observed that NK cells efficiently lysed K562 target cells and that histamine did not affect this NK cell activity. In summary, this is the first demonstration of the protein expression of H4 receptor in NK cells. Also, the results of the chemotactic effects of histamine on NK cells and THP-1 cells are novel. These results may shed some light on the colocalization of cells of innate immune arm at sites of inflammation. They are also important for developing drugs that target H4R for the treatment of various disorders, such as autoimmune and immunodeficient diseases.

Topics: Calcium; Cell Line; Chemotaxis; Clone Cells; Dendritic Cells; Dose-Response Relationship, Drug; Histamine; Humans; Interleukin-2; Killer Cells, Natural; Monocytes; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

The Drosophila melanogaster photoreceptor cell has long served as a model system for researchers focusing on how animal sensory neurons receive information from their surroundings and translate this information into chemical and electrical messages. Electroretinograph (ERG) analysis of Drosophila mutants has helped to elucidate some of the genes involved in the visual transduction pathway downstream of the photoreceptor cell, and it is now clear that photoreceptor cell signaling is dependent upon the proper release and recycling of the neurotransmitter histamine. While the neurotransmitter transporters responsible for clearing histamine, and its metabolite carcinine, from the synaptic cleft have remained unknown, a strong candidate for a transporter of either substrate is the uncharacterized inebriated protein. The inebriated gene (ine) encodes a putative neurotransmitter transporter that has been localized to photoreceptor cells in Drosophila and mutations in ine result in an abnormal ERG phenotype in Drosophila. Loss-of-function mutations in ebony, a gene required for the synthesis of carcinine in Drosophila, suppress components of the mutant ine ERG phenotype, while loss-of-function mutations in tan, a gene necessary for the hydrolysis of carcinine in Drosophila, have no effect on the ERG phenotype in ine mutants. We also show that by feeding wild-type flies carcinine, we can duplicate components of mutant ine ERGs. Finally, we demonstrate that treatment with H(3) receptor agonists or inverse agonists rescue several components of the mutant ine ERG phenotype. Here, we provide pharmacological and genetic epistatic evidence that ine encodes a carcinine neurotransmitter transporter. We also speculate that the oscillations observed in mutant ine ERG traces are the result of the aberrant activity of a putative H(3) receptor.

Topics: Animals; Animals, Genetically Modified; Base Sequence; Carnosine; DNA Primers; DNA-Binding Proteins; Drosophila melanogaster; Drosophila Proteins; Electroretinography; Genes, Insect; Histamine; Histamine H3 Antagonists; Models, Neurological; Mutation; Neuroglia; Neurons, Afferent; Phenotype; Photoreceptor Cells, Invertebrate; Piperidines; Plasma Membrane Neurotransmitter Transport Proteins; Signal Transduction; Synapses

Histamine is a chemical mediator that acts at four known types of histamine receptors and has been widely implicated in the development of nociception and neuropathic pain. Blocking histamine H(1) and H(2) receptors has been shown to reduce hyperalgesia following nerve injury, but the role of histamine H(3) and H(4) receptors in neuropathic pain has not been studied. Here, we used blockers of histamine H(3) and H(4) receptors to assess their effects on neuropathic pain behavior and mast cell numbers following peripheral nerve injury. In addition, we assessed the effect of activating H(4) receptors on neuropathic pain behavior.. Rats were subjected to a partial ligation of the sciatic nerve, a model of neuropathic pain, and were treated either systemically or locally (hindpaw) with the H(3)/H(4) receptor inverse agonist thioperamide, the specific H(4) receptor antagonist JNJ 7777120, or the H(4) receptor agonist VUF 8430. Measurements of mechanical hyperalgesia were carried out by Randall-Selitto test for 1-3 weeks, and sciatic nerve tissues were analyzed for numbers of intact mast cells by histology at 9 h after surgery.. Rats treated with thioperamide or JNJ 7777120 showed significantly enhanced mechanical hyperalgesia after partial ligation of the sciatic nerve. The number of intact mast cells in the injured nerve of these rats was higher than in control rats suggesting reduced mast cell degranulation, but was still significantly lower than in intact nerves. Rats treated with VUF 8430 showed significantly reduced mechanical hyperalgesia.. We propose that the increase in mechanical hyperalgesia produced by thioperamide and JNJ 7777120 and the decrease in mechanical hyperalgesia produced by VUF 8430 may represent a direct effect of these agents on mechanospecific primary afferents, or an indirect effect of these agents via injury-induced inflammation.

Topics: Animals; Guanidines; Histamine Antagonists; Hyperalgesia; Indoles; Ligation; Male; Mast Cells; Neuralgia; Pain Threshold; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Sciatic Nerve; Thiourea

To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.. Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.. (1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.. Brain histamine H3 receptors may be related to asthmatic respiratory responses.

Topics: Animals; Asthma; Brain; Guinea Pigs; Histamine Agonists; Histamine H3 Antagonists; Lateral Ventricles; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine H3; Substance P; Trachea

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.

Topics: Animals; Avoidance Learning; Convulsants; Donepezil; Electric Stimulation; Female; Histamine Antagonists; Indans; Kindling, Neurologic; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Nootropic Agents; Pentylenetetrazole; Piperidines; Recognition, Psychology

Complications of sickle cell anaemia include vascular occlusion triggered by the adherence of sickle erythrocytes to endothelium in the postcapillary venules. Adherence can be promoted by inflammatory mediators that induce endothelial cell adhesion molecule expression and arrest flowing erythrocytes. The present study characterised the effect of histamine stimulation on the kinetics of sickle cell adherence to large vessel and microvascular endothelium under physiological flow. Increased sickle cell adherence was observed within minutes of endothelial activation by histamine and reached a maximum value within 30 min. At steady state, sickle cell adherence to histamine-stimulated endothelium was 47 +/- 4 adherent cells/mm(2), 2.6-fold higher than sickle cell adherence to unstimulated endothelial cells. Histamine-induced sickle cell adherence occurred rapidly and transiently. Studies using histamine receptor agonists and antagonists suggest that histamine-induced sickle cell adhesion depends on simultaneous stimulation of the H(2) and H(4) histamine receptors and endothelial P-selectin expression. These data show that histamine release may promote sickle cell adherence and vaso-occlusion. In vivo histamine release should be studied to determine its role in sickle complications and whether blocking of specific histamine receptors may prevent clinical complications or adverse effects from histamine release stimulated by opiate analgesic treatment.

Topics: Analysis of Variance; Anemia, Sickle Cell; Cell Adhesion; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Erythrocytes; Famotidine; Histamine; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Imidazoles; Methylhistamines; P-Selectin; Piperidines; Pyrilamine; Stimulation, Chemical; Thiazoles; Thiourea; Venules

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.

Topics: Animals; Cell Death; Cells, Cultured; Coculture Techniques; Convulsants; Hippocampus; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Hypothalamus, Anterior; Hypothalamus, Posterior; Imidazoles; Kainic Acid; Methylhistidines; Microscopy, Confocal; Neurons; Neuroprotective Agents; Organ Culture Techniques; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3; Thiourea; Triprolidine

Phosphodiesterase-4 (PDE4) is one of the main enzymes that specifically terminate the action of cAMP, thereby contributing to intracellular signaling following stimulation of various G protein-coupled receptors. PDE4 expression and activity are modulated by agents affecting cAMP levels. The selective PDE4 inhibitor (R)-rolipram labeled with C-11 was tested in vivo in rats to analyze changes in PDE4 levels following drug treatments that increase synaptic noradrenaline (NA), serotonin (5HT), histamine (HA) and dopamine (DA) levels. We hypothesized that increasing synaptic neurotransmitter levels and subsequent cAMP-mediated signaling would significantly enhance (R)-[(11)C]rolipram retention and specific binding to PDE4 in vivo. Pre-treatments were performed 3 h prior to tracer injection, and rats were sacrificed 45 min later. Biodistribution studies revealed a dose-dependent increase in (R)-[(11)C]rolipram uptake following administration of the monoamine oxidase (MAO) inhibitor tranylcypromine, NA and 5HT reuptake inhibitors (desipramine [DMI], maprotiline; and fluoxetine, sertraline, respectively), and the HA H(3) receptor antagonist (thioperamide), but not with DA transporter blockers GBR 12909, cocaine or DA D(1) agonist SKF81297. Significant increases in rat brain and heart reflect changes in PDE4 specific binding (total-non-specific binding [coinjection with saturating dose of (R)-rolipram]). These results demonstrate that acute treatments elevating synaptic NA, 5HT and HA, but not DA levels, significantly enhance (R)-[(11)C]rolipram binding. Use of (R)-[(11)C]rolipram and positron emission tomography as an index of PDE4 activity could provide insight into understanding disease states with altered NA, 5HT and HA concentrations.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Brain; Cyclic Nucleotide Phosphodiesterases, Type 4; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Heart; Histamine; Lung; Male; Myocardium; Neurotransmitter Agents; Norepinephrine; Phosphodiesterase Inhibitors; Piperidines; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Rolipram; Selective Serotonin Reuptake Inhibitors; Serotonin; Synapses; Tranylcypromine

The effects of histamine (HA) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay (RIA) after a 1 or 2-h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following HA administration, depending on the HA dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the HA antagonist mepyramine (MEP, an H1 receptor antagonist) or cimetidine (CIM, an H2 receptor antagonist). Thioperamide (TPE, an H3-H4 receptor antagonist) did not influence the VP or OT secretion increase induced by HA. The application of MEP, CIM or TPE after HA administration proved ineffective. The H1 and H2 receptors are mainly involved in the HA-induced increase of both VP and OT secretion in isolated NH tissue cultures. The results indicate that NH hormone release is influenced directly by the histaminergic system, and the histaminergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Topics: Animals; Cimetidine; Dose-Response Relationship, Drug; Histamine; Histamine Antagonists; Kinetics; Male; Oxytocin; Piperidines; Pituitary Gland, Posterior; Pyrilamine; Rats; Tissue Culture Techniques; Vasopressins

To determine how the histaminergic system is implicated in vestibular compensation, we studied the changes in histidine decarboxylase (HDC; the enzyme synthesizing histamine) mRNA regulation in the tuberomammillary (TM) nuclei of cats killed 1 week, 3 weeks and 3 months after unilateral vestibular neurectomy (UVN). We also used one- and two-step bilateral vestibular neurectomized (BVN) cats to determine whether HDC mRNA regulation depended on the asymmetrical vestibular input received by the TM nuclei neurons. In addition, we analysed the HDC mRNA changes in the TM nuclei and the recovery of behavioural functions in UVN cats treated with thioperamide, a pure histaminergic drug. Finally, we quantified binding to histamine H3 receptors (H3Rs) in the medial vestibular nucleus (VN) by means of a histamine H3R agonist ([3H]N-alpha-methylhistamine) in order to further investigate the sites and mechanisms of action of histamine in this structure. This study shows that UVN increases HDC mRNA expression in the ipsilateral TM nucleus at 1 week. This increased expression persisted 3 weeks after UVN, and regained control values at 3 months. HDC mRNA expression was unchanged in the one-step BVN cats but showed mirror asymmetrical increases in the two-step BVN compared to the 1 week UVN cats. Three weeks' thioperamide treatment induced a bilateral HDC mRNA up-regulation in the UVN cats, which was higher than in the untreated UVN group. Binding to histamine H3Rs in the MVN showed a strong bilateral decrease after thioperamide treatment, while it was reduced ipsilaterally in the UVN cats. That such changes of the histaminergic system induced by vestibular lesion and treatment may play a functional role in vestibular compensation is strongly supported by the behavioural data. Indeed, spontaneous nystagmus, posture and locomotor balance were rapidly recovered in the UVN cats treated with thioperamide. These results demonstrate that changes in histamine levels are related to vestibular compensation.

Topics: Adaptation, Physiological; Animals; Binding Sites; Cats; Functional Laterality; Gene Expression Regulation; Histamine; Histamine Agonists; Histamine Antagonists; Histidine Decarboxylase; Hypothalamic Area, Lateral; Methylhistamines; Motor Activity; Nystagmus, Pathologic; Piperidines; Postural Balance; Receptors, Histamine H3; RNA, Messenger; Time Factors; Vestibular Nerve; Vestibule, Labyrinth

Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H(3) receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20 mg/kg thioperamide and saline or 8 mg/kg cocaine, 10 min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8 mg/kg, i.p.) given 2 and 14 days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20 mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32 mg/kg, s.c.), the drugs being given 10 min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14 days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H(3) receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies.

Topics: Animals; Cocaine; Dose-Response Relationship, Drug; Drug Synergism; Histamine Antagonists; Male; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Psychomotor Performance; Receptors, Histamine H3; Stereotyped Behavior

We previously described that agonist-activated histamine H3 autoreceptors inhibit the stimulation of histamine synthesis mediated by calcium/calmodulin- and cAMP-dependent protein kinases (CaMKII and PKA respectively) in histaminergic nerve endings. In the absence of an agonist H3 receptors show partial constitutive activity, so we hypothesized that suppression of constitutive activity by an inverse agonist could stimulate these transduction pathways. We show here that the H3 inverse agonist thioperamide increases histamine synthesis in rat brain cortical slices independently from the amounts of extracellular histamine. Thioperamide effects were mimicked by the inverse agonists clobenpropit and A-331440, but not by the neutral antagonist VUF-5681. In contrast, coincubation with VUF-5681 suppressed thioperamide effects. The effects of thioperamide were completely blocked by the PKA inhibitor peptide myristoyl-PKI14-22, a peptide that did not block depolarization stimulation of histamine synthesis. In addition, thioperamide effects required depolarization and were impaired by blockade of N-type calcium channels (mediating depolarization), but not by CaMKII inhibition. These results indicate that constitutive activity of H3 receptors in rat brain cortex inhibits the adenylate cyclase/PKA pathway, and perhaps also the opening of N-type voltage sensitive calcium channels, but apparently not CaMKII.

Topics: Animals; Biphenyl Compounds; Brain; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Male; Models, Biological; Nitriles; Piperidines; Potassium; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Thiourea

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Catalepsy; Dose-Response Relationship, Drug; Haloperidol; Histamine Agonists; Histamine Antagonists; Methylhistamines; Mice; Models, Animal; Motor Activity; Piperidines; Receptors, Histamine H3; Schizophrenia; Stereotyped Behavior; Time Factors

Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of histamine. The present study examined the physiological role of H3Rs in drinking behavior. In water-replete rats, intracerebroventricular (i.c.v.) administration of R-alpha-methylhistamine (RalphaMeHA), an H3R agonist, elicited drinking behavior. In contrast, i.c.v. administration of thioperamide, an H3R inverse agonist, significantly attenuated the drinking behavior elicited by either overnight dehydration or i.c.v. administration of angiotensin-II (AT-II). Inhibition of histamine release with alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not elicit drinking behavior. Moreover, the inhibitory effects of thioperamide on drinking behavior in water-depleted rats were not mimicked by i.c.v. administration of histamine. These results suggest that the predominant effects of H3Rs on drinking behavior are not mediated by the modulation of histamine release. In H3R-deficient (H3RKO) mice, drinking behavior induced by overnight dehydration or i.c.v. administration of AT-II was significantly impaired compared to wild type mice. Collectively, these observations suggest that brain H3Rs play a pivotal role in drinking behavior in response to dehydration and AT-II, and these effects may be largely independent of the modulation of histaminergic tone.

Topics: Angiotensin II; Animals; Behavior, Animal; Dehydration; Drinking Behavior; Male; Methylhistamines; Mice; Mice, Knockout; Piperidines; Rats; Receptors, Histamine H3; Time Factors

An increase in the histamine concentration in the brain has been demonstrated to provide protective effects against ischemia/reperfusion brain injury. Since hypothermia and barbiturates are also regarded to protect ischemic brains, effects of postischemic treatments were compared in gerbils between mild hypothermia and intraperitoneal administration of L-histidine, a precursor of histamine. Furthermore, effects of thioperamide, a histamine H(3) receptor antagonist, were evaluated in histidine-treated gerbils after 60 days. Transient forebrain ischemia for 4 min at 37 degrees C provoked severe neuronal damage in the hippocampal CA1 pyramidal cells after 7 days. Postischemic hypothermia (33 degrees C) for 3 h under pentobarbital anesthesia alleviated neuronal death, and the number of preserved neurons was 77+/-56/mm (mean+/-S.D., n=14). The effect of L-histidine injected three times, immediately, 6 h, and 24 h after reperfusion (1,000 mg/kg, i.p., each), was more prominent than that of hypothermia, and the number of preserved neurons was 142+/-55/mm (n=14). When the histologic outcome was evaluated after 60 days, most neurons were damaged in both the hypothermic and histidine groups. The improvement of the histologic outcome was observed even after 60 days in animals injected with thioperamide, immediately and 6 h after reperfusion (5 mg/kg, s.c., each), with three injections of l-histidine. The number of preserved neurons was 133+/-88/mm (n=10), while that in the hypothermic group was 7+/-15 (n=10). Activation of the central histaminergic system provides beneficial effects against cerebral ischemia.

Topics: Animals; Brain Ischemia; Drug Therapy, Combination; Gerbillinae; Hippocampus; Histamine; Histamine Antagonists; Histidine; Hypnotics and Sedatives; Hypothermia, Induced; Male; Neuroprotective Agents; Pentobarbital; Piperidines; Prosencephalon; Pyramidal Cells; Reperfusion Injury; Time Factors

We examined the renoprotective effects of l-carnosine (beta-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N-alpha-Acetyl-l-carnosine [N-acetyl-beta-alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H(3) receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H(3) receptor agonist, R-alpha-methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H(3) receptors in the central nervous system.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Carnosine; Histidine; Injections, Intraventricular; Kidney; Male; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sympathetic Nervous System

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in L-dihydroxyphenylalanine (L-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D(1)/D(5) receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Animals, Newborn; Benzazepines; Catalepsy; Corpus Striatum; Dialysis Solutions; Dopamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Mastication; Microdialysis; Motor Activity; Oxidopamine; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Stereotyped Behavior; Thiourea

Previous studies have demonstrated that central injection of orexin-A affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in both anesthetized and unanesthetized rats. In the present study, we examined, using urethane-anesthetized rats, the dose-dependent effects of intravenous (iv) or intralateral cerebral ventricular (LCV) injection of various doses of orexin-A on RSNA and BP. We found that injection of a low dose of orexin-A (10 ng iv or 0.01 ng LCV) suppressed RSNA and BP significantly. Conversely, a high dose (1000 ng iv or 10 ng LCV) of orexin-A elevated both RSNA and BP significantly. Pretreatment with either iv or LCV injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of orexin-A on both RSNA and BP. Both iv and LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of orexin-A on RSNA and BP. Furthermore, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of both low and high doses of orexin-A on RSNA and BP. These findings suggest that orexin-A affects RSNA and BP in a dose-dependent manner and that the SCN and histaminergic nerve may be involved in the dose-different effects of orexin-A in rats.

Topics: Anesthetics, Intravenous; Animals; Blood Pressure; Cerebral Ventricles; Dose-Response Relationship, Drug; Histamine Agonists; Hypothalamus; Intracellular Signaling Peptides and Proteins; Kidney; Neuropeptides; Orexins; Piperidines; Rats; Rats, Sprague-Dawley; Suprachiasmatic Nucleus; Sympathetic Nervous System; Time Factors; Urethane

Chemosensory information from peripheral arterial oxygen sensors in the carotid body is relayed by petrosal ganglion neurons to the respiratory networks in the medulla oblongata. Biogenic amines, including histamine, released from glomus (type I) cells of the carotid body are considered to be primary transmitters in hypoxic chemosensitivity. Immunocytochemistry at light-and electron-microscopical levels, and RT-PCR, revealed the expression of histamine receptors 1 and 3 as well as histidine decarboxylase in the rat carotid body glomus cells and petrosal ganglion neurons. Histamine receptors 1 and 3, but not histidine decarboxylase, were also observed in the ventrolateral, intermediate and commissural subnuclei of the nucleus tractus solitarii in the medulla oblongata. In order to examine the possible role of histamine in the afferent branch of the respiratory system, we applied histamine receptor 1 and 3 agonists to the carotid body, which caused a mildly increased phrenic nerve activity in a working heart-brainstem preparation. Moreover, microinjection of antagonists of histamine receptors 1 and 3 into the nucleus tractus solitarii caused significant changes in the inspiratory timing and the chemoreceptor response. Our data show that histamine acting via histamine receptors 1 and 3 plays an important neuromodulatory role in the afferent control of chemosensitivity.

Topics: Afferent Pathways; Amidines; Animals; Blotting, Northern; Carotid Body; Chemoreceptor Cells; Female; Gene Expression; Histamine; Histamine Antagonists; Histidine Decarboxylase; Immunohistochemistry; Male; Medulla Oblongata; Microscopy, Immunoelectron; Phrenic Nerve; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Respiration; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Cyanide

It is assumed that an overproduction of gastric acid is the most important factor in the development of peptic ulcer. However, it has been also demonstrated that gastric defense mechanisms, which prevent mucosal injury, are enhanced by the same factors that increase acid secretion. The aim of this study was to examine the role of capsaicin-sensitive sensory nerves and histamine H1, H2, and H3 receptors in histamine-induced gastroprotection against stress ulcers. Studies were performed on rats with intact or ablated sensory nerves. Ablation of sensory nerves was induced by neurotoxic doses of capsaicin. Gastric ulcers were induced by water immersion and restrain stress. Before exposure to stress, rats were pretreated with saline (control), histamine (10 micromol/kg), histamine H1 receptor antagonist pyrilamine (100 micromol/kg), histamine H2 receptor antagonist ranitidine (100 micromol/kg), histamine H3 receptor antagonist thioperamide (100 micromol/kg), or a combination of histamine with these histamine receptor antagonists.. Histamine alone reduced ulcer area evoked by stress and this effect was accompanied by an increase in gastric mucosal blood flow and mucosal DNA synthesis, as well as a decrease in serum pro-inflammatory interleukin-1beta concentration. Treatment with combination of pyrilamine plus histamine caused an increase in gastric ulcer area and serum interleukin-1beta above the value observed in animals treated with saline, and this effect was accompanied by a decrease in gastric mucosal DNA synthesis. Ranitidine, in combination with histamine, reduced the ulcer area and serum interleukin-1beta to a minimal value, whereas gastric mucosal blood flow and DNA synthesis reached a maximal value. Pretreatment with thioperamide before histamine administration abolished the histamine-evoked reduction in gastric ulcer area. Ablation of sensory nerves increased the ulcer area in animals treated with saline or histamine, or histamine in combination with pyrilamine or ranitidine. In animals with sensory nerves ablation combined with administration of thioperamide plus histamine, the ulcer area was similar to that in saline-treated animals with intact sensory nerves. We conclude that: (1) histamine exhibits protective effect against stress-induced gastric ulcer and that this gastroprotection is related to stimulation of histamine H1 and H3 receptors; (2) blockade of histamine H2 receptors exhibited beneficial effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors.

Topics: Animals; Capsaicin; DNA; Gastric Mucosa; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Immersion; Interleukin-1; Male; Neurons, Afferent; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Regional Blood Flow; Restraint, Physical; Stomach Ulcer; Stress, Physiological

The pharmacological consequences of combining a histamine H1 receptor antagonist with a H3 antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H1 antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 +/- 4, 31 +/- 4, 32 +/- 4 and 37 +/- 4%, respectively. Combination treatment with an H1 and H3 antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H3 antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 +/- 4, 45 +/- 4, 49 +/- 4 and 54 +/- 4%. A second H3 antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H1 and a H3 histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H1 or H3 antagonist administered separately. In addition, the antiallergy activity of combining a H3 antihistamine with a H3 antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.

Topics: Animals; Capillary Permeability; Chlorpheniramine; Drug Synergism; Guinea Pigs; Histamine Antagonists; Histamine H1 Antagonists; Histamine Release; Injections, Intradermal; Injections, Intravenous; Male; p-Methoxy-N-methylphenethylamine; Piperidines; Receptors, Histamine H1; Receptors, Histamine H3; Skin

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Topics: Animals; Cognition Disorders; Discrimination Learning; Escape Reaction; Histamine Antagonists; Imidazoles; Male; Maze Learning; Mice; Mice, Inbred C57BL; Models, Animal; Muscarinic Antagonists; Piperidines; Rats; Rats, Long-Evans; Receptors, Histamine H3; Scopolamine; Spatial Behavior

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H1 and H2 antagonists having been found to potentiate conditioned place preference induced by morphine or cocaine. In contrast, the role of H3 receptors in cocaine-induced place preference is still unknown. The present study tested the effects of thioperamide (0, 10 and 20 mg/kg, i.p.), an H3 autoreceptor antagonist, on the development of a conditioned place preference induced by cocaine (0, 2 and 8 mg/kg, i.p.) in C57BL/6J mice. Thioperamide was injected 10 min before each cocaine-pairing session. The activity scores recorded on the first cocaine-pairing session were also used to test the effects of thioperamide on cocaine-induced locomotor activity. Thioperamide alone had no reinforcing effects and did not affect the conditioned place preference induced by 8 mg/kg cocaine. However, thioperamide dose-dependently revealed a conditioned place preference induced by 2 mg/kg cocaine, a dose that was inactive per se. Finally, thioperamide dose-dependently potentiated the stimulant effects of cocaine, in spite of its slight hypolocomotor effect when given alone. Our results strongly suggest that H3 antagonists potentiate the stimulant and reinforcing effects of cocaine in mice.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cocaine; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Histamine Antagonists; Locomotion; Male; Mice; Mice, Inbred C57BL; Piperidines; Receptors, Histamine H3; Reinforcement, Psychology

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Topics: Animals; Antipsychotic Agents; Benzofurans; Brain Chemistry; Cataplexy; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Synergism; Haloperidol; Histamine; Histamine Antagonists; Imidazoles; Ketoconazole; Male; Metabolic Clearance Rate; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Risperidone; Schizophrenia

Using a cyanide model to induce neurotoxic effects in rat brain homogenates, we examined the neuroprotective properties of three H3 antagonists, namely clobenpropit, thioperamide and impentamine, and compared them to aspirin, a known neuroprotective agent. Superoxide anion levels and malondialdehyde concentration were assessed using the nitroblue tetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Impentamine reduced lipid peroxidation at all concentrations used, but only reduced superoxide anion generation at a concentration of 1 mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. This study demonstrates the potential of these agents to be neuroprotective by exerting antioxidant effects.

Topics: Animals; Antioxidants; Aspirin; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine Agonists; Imidazoles; In Vitro Techniques; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Potassium Cyanide; Rats; Rats, Wistar; Receptors, Histamine H3; Superoxides; Thiourea

A combination of sub-effective doses of thioperamide (7.5 mg/kg, i.p.) and tacrine (0.5 mg/kg, i.p.) enhanced performance in a spatial memory task in mice. This was shown by a significant increase in their spontaneous alternation scores in a cross maze test.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Histamine Antagonists; Injections, Intraperitoneal; Male; Maze Learning; Mice; Parasympathomimetics; Piperidines; Psychomotor Performance; Tacrine

This study was designed i) to investigate the role of histamine H3-receptor ligands on mouse modified forced swimming test, a method that distinguishes the catecholaminergic behaviour with that of serotonergic compounds and ii) to evaluate the role of free radicals in mediation of such effects. Swiss strain albino mice were treated with different doses of histamine H3-receptor antagonist thioperamide (3.75, 7.5 and 15 mg/kg intraperitoneally) and agonist (R)-alpha-methylhistamine (5 microg intracerebroventricularly). The climbing, swimming and immobility times were recorded for 6 min. Immediately after modified forced swimming test, the animals were sacrificed and parameters of oxidative stress were assessed in the brain by measuring the thiobarbituric acid reactive substance (TBARS), glutathione (GSH) and catalase levels. Thioperamide (7.5 and 15 mg/kg intraperitoneally) dose-dependently decreased immobility time and increased swimming time but not climbing time. The behaviour of mice treated with (R)-alpha-methylhistamine was similar to that of control mice. A significant reduction in GSH and an increase in catalase levels were observed in brains of mice exposed to modified forced swimming test. Thioperamide pretreatment dose-dependently reversed such an alteration in oxidative stress parameters. (R)-alpha-methylhistamine caused a reversal of altered catalase but not GSH levels. Thioperamide shows antidepressant effects in the modified forced swimming test and causes a reversal of the test-induced oxidative stress indicating its antioxidant potential. The antidepressant effect of thioperamide appears to be mediated via serotonergic and/or antioxidant mechanisms.

Topics: Animals; Antidepressive Agents; Brain; Catalase; Female; Glutathione; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Mice, Inbred Strains; Motor Activity; Oxidative Stress; Piperidines; Receptors, Histamine H3; Swimming; Thiobarbituric Acid Reactive Substances

Although the effectiveness of histamine-related drugs in the treatment of peripheral and central vestibular disorders may be explained by their action on the vestibular nuclei, it has also been shown that antivertigo effects can take place at the peripheral level. In this work, we examined the actions of H3 histaminergic agonists and antagonists on the afferent neuron electrical discharge in the isolated inner ear of the axolotl. Our results indicate that H3 antagonists such as thioperamide, clobenpropit, and betahistine (BH) decreased the electrical discharge of afferent neurons by interfering with the postsynaptic response to excitatory amino acid agonists. These results lend further support to the idea that the antivertigo action of histamine-related drugs may be caused, at least in part, by a decrease in the sensory input from the vestibular endorgans. The present data show that the inhibitory action of the afferent neurons discharge previously described for BH is not restricted to this molecule but is also shared by other H3 antagonists.

Topics: Afferent Pathways; Ambystoma; Animals; Betahistine; Dose-Response Relationship, Drug; Hair Cells, Auditory; Histamine Agents; Histamine Agonists; Histamine Antagonists; Imidazoles; Neural Inhibition; Piperidines; Receptors, Glutamate; Receptors, Histamine H3; Semicircular Canals; Signal Transduction; Thiourea; Vestibular Nerve; Vestibule, Labyrinth

Inflammation is a factor in the aggravation of reperfusion injury after cerebral ischemia. Since histamine H(2) receptor stimulation suppresses inflammatory reactions, effects of the central histaminergic activation on brain infarction were examined in rats. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery, and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride stain after 24 h. Effects of postischemic administration of thioperamide, an H(3) antagonist, and metoprine, an inhibitor of histamine-N-methyltransferase, were evaluated in rats treated with l-histidine, a precursor of histamine. Furthermore, effects of these agents on changes in the striatal histamine level were examined by a microdialysis procedure. Focal ischemia provoked marked damage in rats treated with l-histidine (1000 mg/kg) alone. Administration of l-histidine (1000 mg/kg) with either thioperamide (5 mg/kg) or metoprine (10 mg/kg) alleviated brain infarction. The size of brain infarction was 27% and 10% of that in animals treated solely with l-histidine, respectively. The combination treatment with thioperamide and metoprine decreased the size of brain infarction in rats given l-histidine (500 mg/kg), although protective effects were not clear without l-histidine. A marked increase in the histamine concentration was observed in the histidine plus metoprine group, the value being 363% of that in the saline-injected group after 2-3 h. The histamine concentrations in the histidine group and histidine plus thioperamide group were 188% and 248%, respectively. These findings indicate that facilitation of central histaminergic activity reduced the brain infarction.

Topics: Animals; Cerebral Infarction; Extracellular Space; Histamine; Histamine Antagonists; Histidine; Male; Piperidines; Pyrimethamine; Rats; Rats, Wistar

Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.

Topics: Adrenergic Uptake Inhibitors; Analysis of Variance; Animals; Behavior, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Synergism; Histamine Antagonists; Imidazoles; Male; Methamphetamine; Microdialysis; Nucleus Accumbens; Piperidines; Rats; Rats, Sprague-Dawley; Self Administration; Thiourea; Time Factors

Histamine is one of the most common chemical mediators causing pruritus, and H1 receptor antagonists have been used as a first choice in its treatment. On the other hand, although the presence of H3 receptors has been identified in the skin, few studies have investigated the involvement of H3 receptors on pruritus.. The purpose of this study was to examine whether H3 receptor agonist or antagonist influences the incidence of scratching behaviour in ICR or mast cell-deficient WBB6F1-W/WV mice.. The mice were given an intradermal injection of H3 receptor agonist or antagonist into the rostral part of the back, and the occurrence of scratching behaviour at the injected site by the hind paws was counted over 60 min.. H3 receptor antagonists, thioperamide and AQ0145 significantly increased the incidence of scratching behaviour in ICR mice. H3 receptor agonist, (R)-alpha-methylhistamine, had no effect. On the other hand, (R)-alpha-methylhistamine significantly inhibited thioperamide or AQ0145-induced scratching behaviour. In addition, both thioperamide and AQ0145 elicited scratching behaviour in mast cell-deficient WBB6F1-W/WV mice.. From these results, it may be concluded that H3 receptors are involved in the modulation of pruritus in the skin, and mast cells are not essential in this response. In addition, H3 receptor agonists can be useful as a novel therapeutic approach against pruritus.

Topics: Adamantane; Amidines; Animals; Female; Histamine Agonists; Histamine H2 Antagonists; Imidazoles; Mast Cells; Methylhistamines; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Piperidines; Pruritus; Receptors, Histamine H3; Skin

Topics: Amygdala; Animals; Histamine Antagonists; Histamine Release; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.

Topics: Acoustic Stimulation; Animals; Dopamine Antagonists; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Histamine Antagonists; Imidazoles; Inhibition, Psychological; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Piperidines; Receptors, Histamine H3; Reflex, Startle; Risperidone; Species Specificity

The central histamine 3 receptor (H3R) is a presynaptic autoreceptor that regulates neuronal release and synthesis of histamine, and is thought to play a key role in controlling numerous central nervous system (CNS)-mediated parameters, including energy homeostasis. Thioperamide, the prototypical selective H3R antagonist, was used to examine the role that H3R plays in regulating energy balance in vivo. Thioperamide was administered either intraperitoneally or orally to rats and the pharmacokinetic parameters were examined along with central H3R binding and histaminergic system activation. Food intake and metabolic parameters of either route of thioperamide administration were likewise examined. In a dose-dependent manner, both the intraperitoneal and oral route of administration resulted in similar ex vivo binding curves and tele-methylhistamine dose-response curves despite the route of administration. However, only intraperitoneal administration of 30 mg/kg thioperamide resulted in a significant decrease in 24-h food intake (60% lower than control) and respiratory quotient (RQ), while the oral route of delivery did not. Moreover, the decrease in RQ with the 30 mg/kg ip administration also decreased energy expenditure (EE) thus resulting in an unchanged energy balance. The decrease in food intake and EE was coupled with a conditioned taste aversion with the 30-mg/kg ip administration. These data indicate that the activation of the central H3R system by thioperamide does not play a direct role in decreasing food intake or altering energy homeostasis.

Topics: Animals; Darkness; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Male; Photoperiod; Piperidines; Protein Binding; Rats; Rats, Long-Evans; Receptors, Histamine H3

Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine that is constitutively expressed by the liver parenchymal cells and present in the normal plasma at high concentrations. Previous studies have shown that CCL16 is a low-affinity ligand for CCR1, CCR2, CCR5, and CCR8 and attracts monocytes and T cells. Recently, a novel histamine receptor termed type 4 (H4) has been identified and shown to be selectively expressed by eosinophils and mast cells. In this study, we demonstrated that CCL16 induced pertussis toxin-sensitive calcium mobilization and chemotaxis in murine L1.2 cells expressing H4 but not those expressing histamine receptor type 1 (H1) or type 2 (H2). CCL16 bound to H4 with a K(d) of 17 nM. By RT-PCR, human and mouse eosinophils express H4 but not H3. Accordingly, CCL16 induced efficient migratory responses in human and mouse eosinophils. Furthermore, the responses of human and mouse eosinophils to CCL16 were effectively suppressed by thioperamide, an antagonist for H3 and H4. Intravenous injection of CCL16 into mice induced a rapid mobilization of eosinophils from bone marrow to peripheral blood, which was also suppressed by thioperamide. Collectively, CCL16 is a novel functional ligand for H4 and may have a role in trafficking of eosinophils.

Topics: Animals; Bone Marrow; Calcium Signaling; Cell Line; Chemokines, CC; Chemotaxis, Leukocyte; Eosinophils; Evolution, Molecular; Humans; Leukocyte Count; Ligands; Liver; Mice; Pertussis Toxin; Phylogeny; Piperidines; Protein Binding; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Recombinant Proteins

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later. More specifically, the following effects of thioperamide (1.25-20 mg/kg) were dose-dependently analysed: (1) its potential direct effects on memory consolidation; (2) its potential reversing effects on retrograde amnesia induced by the NMDA antagonist dizocilpine (MK-801, 0.5 mg/kg) and (3) its potential reversing effects on the well-known amnesia induced by the muscarinic antagonist scopolamine (0.25 mg/kg). We found that thioperamide exerted a dose-dependent facilitative effect on memory consolidation. Furthermore, the H3 receptor antagonist reversed scopolamine- and especially dizocilpine-induced amnesia. The results strongly support the view that the brain mechanisms of memory consolidation involve a functional interaction between the NMDA and the H3 sites.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Memory; Mice; Mice, Inbred C57BL; Piperidines; Reaction Time; Scopolamine

There is evidence that histamine H3 receptors co-localise with dopamine D1 receptors on the terminals of striato-nigral neurones. In this work we studied the effect of the local activation of H3 receptors present in substantia nigra pars reticulata (SNr) on turning behaviour following apomorphine administration to either naive or hemiparkinsonian rats. In naive rats the intranigral (SNr) injection of the H3 receptor agonist immepip (3.2 or 32 ng/1 microl) resulted in ipsilateral turning following systemic apomorphine (0.5 mg/kg, subcutaneous). The effect of immepip was related to the dose and prevented by the H3 antagonist thioperamide (5 mg/kg, intraperitoneal). Conversely, in rats with 6-hydroxydopamine (6-OHDA) lesions to either substantia nigra pars compacta or the medial forebrain bundle (mfb), apomorphine-induced contralateral turning was reduced by intranigral immepip, an effect prevented by systemic thioperamide. Our data show that H3 receptors present in SNr regulate the synaptic output of the basal ganglia, most likely by reducing GABA release from striato-nigral terminals. These results may be relevant for the understanding of the role of histamine and H3 receptors in the control of motor behaviour both in normal and pathophysiological conditions, such as Parkinson's disease in which histaminergic innervation and histamine levels in substantia nigra have been shown to increase.

Topics: Analysis of Variance; Animals; Apomorphine; Behavior, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Functional Laterality; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Motor Activity; Oxidopamine; Piperidines; Rats; Rats, Wistar; Stereotyped Behavior; Substantia Nigra

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Topics: Amygdala; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Epilepsy, Tonic-Clonic; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Isothiuronium; Kindling, Neurologic; Lateral Ventricles; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

The existence of mouse H3-receptor isoforms was investigated by PCR analysis and cDNA cloning. Splicing mechanisms previously reported in various species are conserved in the mouse. The retention/deletion of a fragment in the third intracellular loop of the mouse receptor leads to the existence of three isoforms designated mH(3(445)), mH(3(413)) and mH(3(397)) according to the length of their deduced amino acid sequence. PCR analysis showed that mouse H3-receptor isoforms display different expression patterns in the brain. Following expression in Cos-1 cells, [125I]iodoproxyfan binding indicated similar pharmacological profiles of the mH(3(445)), mH(3(413)) and mH(3(397)) isoforms. The pharmacological profile of the mouse H3 receptor is more similar to the rat receptor than to the human receptor, although some differences were also observed between the mouse and rat receptors. For example, the potency of thioperamide and ciproxifan is slightly higher at the mouse receptor than at the rat receptor but 40-100-fold higher than at the human receptor. In situ hybridization histochemistry showed that the distribution of H3-receptor mRNAs in the mouse brain is rather similar to that previously reported in the rat brain. However, the autoradiographic and cellular expression patterns observed in several brain areas such as the thalamus or hippocampus reveal important differences between the two species.

Topics: Animals; Blotting, Northern; Brain; Chlorocebus aethiops; Cloning, Molecular; Competitive Bidding; COS Cells; Gene Expression; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; In Situ Hybridization; Iodine Radioisotopes; Isoenzymes; Mice; Piperidines; Radioligand Assay; Rats; Receptors, Histamine H3; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiourea; Transfection

Theoretically, the overall effect of histamine on respiratory smooth muscle is the result of a subtle balance of contraction and relaxation. The aim of the study was to identify histamine type 2 (H2) and 3 (H3) receptor-dependent relaxing mechanisms in the contractile elements of the bovine tracheobronchial tree. In bronchial preparations, histamine induced very weak contractions, which were not exacerbated with the H2-antagonist cimetidine. Moreover, precontracted bronchial rings never relaxed in response to cumulative doses of histamine or amthamine (H2-agonist). In intact tracheal preparations, histamine induced strong contractions that were exacerbated by cimetidine (E(max): +17.2+/-6.6%) but not by thioperamide (H3-antagonist). Precontracted tracheal bundles did not relax in response to cumulative doses of the H3-agonist R-alpha-methylhistamine. The tracheal contractile response was higher in denuded compared to intact preparations (11.0+/-1.2 vs. 6.0+/-1.7 g). Cimetidine effect was dramatically potentiated in denuded tracheal strips (+40.0+/-11.7%). It is concluded that the weak response of bovine bronchi to histamine is due to a relative scarcity of H1 receptors on bronchial smooth muscle rather than to H2- or H3-dependent relaxation. In the bovine trachea, the smooth muscle possesses relaxing H2 but no H3 receptors. The epithelium exercises a relaxation, which is independent from H2 and H3 receptors.

Topics: Animals; Bronchi; Cattle; Cimetidine; Dose-Response Relationship, Drug; Histamine; Histamine H2 Antagonists; Muscle Relaxation; Muscle, Smooth; Piperidines; Receptors, Histamine H2; Receptors, Histamine H3; Respiratory Mucosa; Trachea

Histaminergic modulation of neuronal activity in the respiratory network was investigated under normoxic and hypoxic conditions in the working heart-brainstem preparation of adult mice. Systemic application of histamine, as well as the H-1 and H-3 receptor agonists 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT) and imetit, 0.5-10 micro M, significantly increased the frequency of respiratory burst discharges. Dimaprit, an H-2 receptor agonist, had no effect on respiratory activity. To test for ongoing histaminergic modulation we applied the histamine receptor antagonists pyrilamine (H-1); cimetidine (H-2) and thioperamide (H-3), each 0.5-10 micro M. Only the H-1 receptor antagonist had significant effects, viz. reduction of respiratory frequency and depression of burst amplitude. Underlying effects of histamine receptor activation were identified at the cellular level. Intracellular recordings showed that histamine mediated an increase in synaptic drive potentials in inspiratory neurones while augmentation of inhibitory and excitatory synaptic activity was observed in expiratory neurones. The augmented synaptic depolarisation of inspiratory neurones was blocked by the H-1 receptor antagonist. Histaminergic modulation is also involved in the hypoxic response of the respiratory network. Blockade of H-1 receptors significantly attenuated secondary depression of the biphasic hypoxic responses, while hypoxic augmentation was not affected. We conclude that histamine is a functional neuromodulator, which is tonically active in the respiratory network and is activated further during hypoxia. The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors.

Topics: Animals; Cimetidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Hypoxia; Medulla Oblongata; Mice; Mice, Inbred C57BL; Nerve Net; Neurons; Phrenic Nerve; Piperidines; Pons; Pyrilamine; Receptors, Histamine H3; Respiratory System

Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H(3) receptor antagonists are under clinical investigation for ADHD.. To investigate the potential of thioperamide, a prototypical H(3) receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels.. Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg).. Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint.. H(3) receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD.

Topics: Adrenocorticotropic Hormone; Animals; Animals, Newborn; Attention; Avoidance Learning; Central Nervous System Stimulants; Cocaine; Cognition; Dextroamphetamine; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Methylphenidate; Motor Activity; Piperidines; Rats; Rats, Inbred SHR; Receptors, Histamine H3

Antinociceptive profiles of decursinol were examined in ICR mice. Decursinol administered orally (from 5 to 200 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick and hot-plate tests. In addition, decursinol attenuated dose-dependently the writhing numbers in the acetic acid-induced writhing test. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by decursinol treatment during the both 1st and 2nd phases in a dose-dependent manner. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of TNF-alpha (100 pg), IL-1 beta (100 pg), IFN-gamma (100 pg), substance P (0.7 microg) or glutamate (20 microg) was dose-dependently diminished by decursinol. Intraperitoneal (i.p.) pretreatment with yohimbine, methysergide, cyproheptadine, ranitidine, or 3,7-dimethyl-1-propargylxanthine (DMPX) attenuated inhibition of the tail-flick response induced by decursinol. However, naloxone, thioperamide, or 1,3-dipropyl-8-(2-amino-4-chloro-phenyl)-xanthine (PACPX) did not affect inhibition of the tail-flick response induced by decursinol. Our results suggests that decursinol shows an antinociceptive property in various pain models. Furthermore, antinociception of decursinol may be mediated by noradrenergic, serotonergic, adenosine A(2), histamine H(1) and H(2) receptors.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Analgesics; Animals; Benzopyrans; Butyrates; Cyproheptadine; Dose-Response Relationship, Drug; Glutamic Acid; Histamine H2 Antagonists; Interferon-gamma; Interleukin-1; Male; Methysergide; Mice; Mice, Inbred ICR; Models, Chemical; Naloxone; Narcotic Antagonists; Pain; Piperidines; Protein Kinase C; Ranitidine; Receptors, Adrenergic; Receptors, Histamine; Receptors, Purinergic P1; Receptors, Serotonin; Serotonin Antagonists; Substance P; Theobromine; Tumor Necrosis Factor-alpha; Xanthines; Yohimbine

1. Histamine (0.004-2 microm) induced a concentration-dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay. 2. The histamine-induced eosinophil shape change was completely abolished by thioperamide (10 microm), an H3/H4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 microm), H1 and H2 receptor antagonists, respectively. The H4 receptor agonists, clobenpropit and clozapine (0.004-2 microm), which are also H3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 microm). The H3/H4 receptor agonists, imetit, R-alpha-methyl histamine and N-alpha-methyl histamine (0.004-2 microm) also induced eosinophil shape change. 3. Histamine induced actin polymerisation (0.015-10 microm), intracellular calcium mobilisation (10-100 microm) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004-10 microm) in eosinophils, all of which were inhibited by thioperamide (10-100 microm). In addition, the H4 receptor agonist/H3 receptor antagonist clozapine (20 microm) stimulated a rise in intracellular calcium in eosinophils. 4. Activation of H4 receptors by histamine (1 microm) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1-10 microm) did not directly induce chemotaxis of eosinophils. 5. Pertussis toxin (1 microg ml-1) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a Galphai/o G-protein. 6. This study demonstrates that human eosinophils express functional H4 receptors and may provide a novel target for allergic disease therapy.

Topics: Actins; Calcium; CD11b Antigen; Cell Size; Chemokine CCL11; Chemokines, CC; Chemotaxis; Clozapine; Cytoskeleton; Dose-Response Relationship, Drug; Eosinophils; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; Pertussis Toxin; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Thiourea; Up-Regulation

The recently identified histamine receptor, H4, was shown to be primarily expressed on leukocytes and has been implicated in the activation of lymphocytes, eosinophils, and mast cells in vitro. Its function in vivo, however, has not yet been characterized. We present evidence for a critical role of H4 receptor in the mast cell-dependent recruitment of neutrophils. Mice injected with zymosan into the pleural cavity developed massive neutrophilia within hours after challenge. Neutrophilia was dose-dependently reduced when mice were pretreated with thioperamide, a known H(3/4) receptor antagonist, whereas H1 and H2 receptor antagonists lacked efficacy. Similarly, a 70 to 80% reduction in neutrophils in the pleural cavity compared with wild-type animals was noted in mice lacking mast cells (W/W(v) mice); mice deficient in MyD88 (MyD88(-/-)); a critical component of the signaling cascade of the major receptor for zymosan, toll-like receptor 2 (TLR2); or in mice pretreated with a functionally antagonistic anti-TLR2 antibody. The residual 20% neutrophil infiltration seen in mast cell-deficient and MyD88(-/-) mice was not further reduced by thioperamide. Neutrophilia was completely restored by transferring wild-type bone marrow-derived mast cells into MyD88(-/-) or W/W(v) mice. Interestingly, when neutrophilia was evoked by carrageenan injection, mast cell depletion and thioperamide had no effect. Various inflammatory mediators were detectable in the pleural cavity of zymosan-challenged mice. Upon pretreatment with thioperamide, reduced levels of the neutrophil chemoattractant leukotriene B4 were observed, providing a mechanistic explanation for the prevention of neutrophilia by H4 receptor antagonism.

Topics: Animals; Bone Marrow Cells; Carrageenan; Cimetidine; Cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine Release; Leukotriene B4; Mast Cells; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Piperidines; Pleurisy; Pyrilamine; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Zymosan

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H(1), H(2) and H(3) receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H(1)), ranitidine (H(2)), thioperamide (H(3)) and the selective H(3) receptor agonist, imetit. Results showed that none of the antagonists or the H(3) agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H(3) receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H(1), H(2) and H(3) receptors are not important actors in the regulation of vascular patency permeability, whereas H(3) receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H(2) receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.

Topics: Animals; Burns; Clemastine; Edema; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H3; Regional Blood Flow; Skin; Statistics, Nonparametric; Thiourea

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

Topics: Adjuvants, Anesthesia; Amnesia; Animals; Avoidance Learning; Brain; Dopamine; Dopamine Agents; Histamine Antagonists; Methamphetamine; Mice; Mice, Knockout; Motor Activity; Norepinephrine; Piperidines; Radioligand Assay; Receptors, Histamine H3; Running; Scopolamine; Serotonin

The role of the histaminergic system in the discriminative stimulus effects of cocaine and methamphetamine was examined in rats trained to discriminate between saline and cocaine (10 mg/kg) or methamphetamine (1.0 mg/kg). L-histidine (400 mg/kg), a precursor of histamine, significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. Previous studies have revealed the existence of several histamine receptor types, H1-, H2-, and H3-receptors. These enhancing effects of L-histidine on the discriminative stimulus effects of cocaine and methamphetamine were attenuated by 5.0 mg/kg of pyrilamine (an H1-receptor antagonist), but not by 1.0 mg/kg of zolantidine (an H2-receptor antagonist), suggesting that these enhancing effects of L-histidine were mediated through the activation of H1-receptors. Thioperamide (7.5 mg/kg), an H3-receptor antagonist, also significantly enhanced the discriminative stimulus effects of cocaine and methamphetamine. However, neither pyrilamine nor zolantidine affected the enhancing effects of thioperamide, unlike the results attained with L-histidine. Therefore our findings suggest that the histaminergic system may modify the discriminative stimulus effects of cocaine and methamphetamine mediated through H1- and H3-receptors.

Topics: Animals; Central Nervous System Stimulants; Cocaine; Discrimination Learning; Drug Synergism; Histamine; Histamine Antagonists; Histidine; Male; Methamphetamine; Piperidines; Rats; Rats, Inbred F344; Receptors, Histamine H1; Receptors, Histamine H3

1. The extraneuronal monoamine transporter from rat (EMTr) was heterologously expressed by stable transfection in human embryonic kidney 293 cells and characterized in radiotracer experiments. 2. EMTr-mediated uptake of 1-methyl-4-phenylpyridinium (MPP(+)) was saturable, with a K(m) of 151 micro mol l(-1) and V(max) of 7.5 nmol min(-1) mg protein(-1). 3. Compared to the human orthologue EMTh (gene symbol SLC22A3), EMTr was about two orders of magnitude more resistant to most inhibitors, including disprocynium24 and corticosterone. 4. Strikingly, inhibitors and substrates at low concentration stimulated EMTr-mediated transport above control level with MPP(+) and noradrenaline as substrate, but not with cimetidine. Results were confirmed with EMT from mouse. 5. With different IC(50)-values for different substrates, the standard method to calculate K(i)-values is not applicable. 6. Our experiments suggest that activation is not caused by changes in membrane potential or trans-stimulation. Since the extent of activation depends markedly on the chemical structure of the monitored substrate, involvement of a receptor-mediated signalling pathway or recruitment of transporter reserve are implausible. 7. To explain activation, we present a kinetic model which assumes two binding sites for substrate or inhibitor per transporter entity, possibly resulting from the assembly of homodimers. 8. Activation explains previous reports about inhibitor-insensitive catecholamine transport in rat brain. 9. We speculate that activation may serve to keep the transporter working for specific substrates in the face of inhibitors.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Biological Transport; Cell Line; Cimetidine; Cloning, Molecular; Corticosterone; Dose-Response Relationship, Drug; Gene Expression; Genetic Vectors; Humans; Imidazoles; Kinetics; Mice; Norepinephrine; Organic Cation Transport Proteins; Papaverine; Piperidines; Quinolines; Rats; Thiourea; Transfection; Tritium

Histamine is an aminergic neurotransmitter that is localized in the CNS and in peripheral tissues. To date, four histamine receptors have been identified, and the H3 receptor, which was recently cloned, is predominantly expressed in the CNS. The peripheral functions of histamine have been investigated intensively using available molecular and pharmacological tools, and the molecular identification of the H3 receptor opens up new possibilities for investigating the role of histamine in central tissues. To understand the biological function of the histamine presynaptic autoreceptor H3, we inactivated the receptor through homologous recombination. H3(-/-) mice manifest mild obese phenotypes that are characterized by increases in body weight, food intake, and adiposity and by reductions in energy expenditure. Consistent with these observations, homozygous null mice have insulin and leptin resistance, increased levels of plasma leptin and insulin, and decreased levels of histamine in the hypothalamic/thalamic region of their brains coupled with increased histamine turnover. The expression of UCP1 in brown adipose tissue and of UCP3 in brown adipose tissue, white adipose tissue, and skeletal muscle is decreased in H3(-/-) mutants, and the anorexigenic activity of thioperamide is not observed. These results suggest that neuronal histamine is a mediator of body-weight homeostasis and that neuronal histamine functions through H3 receptors in mice.

Topics: Animals; Biomarkers; Body Weight; Brain; Eating; Female; Gene Targeting; Histamine; Histamine Antagonists; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Muscle, Skeletal; Neurons; Obesity; Phenotype; Piperidines; Receptors, Histamine H3

Histamine H3 receptors modulate histamine synthesis, although little is known about the transduction mechanisms involved. To investigate this issue, we have used a preparation of rat brain cortical miniprisms in which histamine synthesis can be modulated by depolarization and by H3 receptor ligands. When the miniprisms were incubated in presence of forskolin, dibutyryl-cAMP, or 3-isobutyl-1-methylxanthine (IBMX), histamine synthesis was stimulated in 34, 29, and 47%, respectively. These stimulations could be prevented by the selective cAMP protein kinase blocker Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPs). Preincubation with the H3 receptor agonist imetit prevented IBMX- (100% blockade) and forskolin- (70% blockade) induced stimulation of histamine synthesis. The H3 inverse agonist thioperamide enhanced histamine synthesis in the presence of 1 mM IBMX or 30 mM potassium (+47 and +45%, respectively). Similarly, the H3 antagonist clobenpropit enhanced histamine synthesis in the presence of 30 mM potassium (+ 59%). The cAMP-dependent protein kinase blockers Rp-cAMPs and PKI14-22 could impair the effects of thioperamide and clobenpropit, respectively. These results indicate that the adenylate cyclase-protein kinase A pathway is involved in the modulation of histamine synthesis by H3 autoreceptors present in histaminergic nerve terminals.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Brain; Bucladesine; Colforsin; Cyclic AMP; Drug Interactions; Histamine; Imidazoles; In Vitro Techniques; Male; Piperidines; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Thionucleotides; Thiourea

On-line microdialysis of histamine in 10-min samples of the prefrontal cortex of the conscious rat is described. The HPLC-fluorescent assay for histamine in dialysates has been significantly simplified by using only one postcolumn reagent line instead of the three reagent lines described in earlier methods. The method is selective, sensitive (detection limit: 2-3 fmol on column), and linear over a large concentration range. Basal values of histamine decreased to about 50% of basal levels during infusion of tetrodotoxin (5 x 10(-6) M). Handling rats for 15 min increased histamine in dialysates to about 300% of basal levels. When tetrodotoxin (10(-6) M) was applied during handling the increase in histamine release was strongly (about 80%) suppressed. The handling-induced increase in histamine was used as a paradigm to investigate the functional activity of histamine H3 autoreceptors during mild stress or arousal. An H3 receptor specific agonist (alpha-methylhistamine; 10(-5) M) and antagonist (thioperamide; 10(-5) M) were infused into the frontal cortex via the microdialysis probe. The effect of handling on histamine release was potentiated during infusion of thioperamide and fully suppressed during infusion of alpha-methylhistamine. These results clearly illustrate the efficacy of the H3 autoreceptor in modulating stimulated histamine release during natural stimulatory conditions.

Topics: Animals; Autoreceptors; Biological Assay; Chromatography, High Pressure Liquid; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Microdialysis; Neurons; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Histamine H3; Stress, Physiological; Synaptic Transmission; Tetrodotoxin

The contribution of hypothalamic histamine neurons to the central regulation of peripheral lipid metabolism was investigated in rats using in vivo microdialysis system. A bolus infusion of L-histamine at doses of 10--10(3) nmol/rat into the third cerebral ventricle (i3vt) dose-dependently increased glycerol concentration in the perfusate from the epididymal adipose tissue. I3vt infusion of 10(2) nmol/rat thioperamide, an autoinhibitory H(3) receptor antagonist that activates histamine neurons to increase synthesis and release of neuronal histamine, convincingly mimicked histamine action in the augmented lipolysis. Intraperitoneal pretreatment with propranolol, a beta-adrenoceptor antagonist, abolished the thioperamide-induced lipolytic action. An electrophysiological study demonstrated that efferent sympathetic nerves innervating the epididymal fat were activated after the i3vt infusion of thioperamide. Hypothalamic histamine neurons thus regulate peripheral lipid metabolism through the accelerating lipolytic action by activation of sympathetic beta-adrenoceptor.

Topics: Adipose Tissue; Adrenergic beta-Antagonists; Animals; Histamine; Histamine Antagonists; Hypothalamus; Lipolysis; Male; Neurons; Piperidines; Propranolol; Rats; Rats, Wistar; Receptors, Adrenergic, beta

Several lines of evidence have indicated that the central histaminergic system might be involved in learning and memory. The aim of the present study was to ascertain the impact on memory processes of putative histaminergic-cholinergic interactions in the nucleus basalis magnocellularis (NBM) of the rat.. The effects of thioperamide, a histamine H3-receptor antagonist, were studied on the memory performance of rats in a two-trial, delayed, place-recognition task. The drug was injected into the NBM area 2 min prior to the first trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-acquisition treatment), within 30 s from the end of the first trial (0.3, 1.5, 7.5, and 37.5 ng/0.5 microl; post-acquisition treatment), or 2 min prior to the second trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-retrieval treatment).. Post-acquisition intra-NBM injections of 1.5 ng and 7.5 ng, but not of 0.3 ng and 37.5 ng thioperamide, significantly enhanced memory retention in treated rats. The histamine H(3)-receptor blocker exerted pro-cognitive effects only when administered post-acquisition, since both pre-acquisition and pre-retrieval treatments were ineffective. The post-acquisition effect of the drug was time dependent and disappeared when the drug was injected 90 min after the end of the first trial. The U-shaped dose-response relationship and the time dependency of the effect of thioperamide indicated that the drug acts on mechanisms involved in memory consolidation.. The present findings demonstrate that the pro-cognitive effect of thioperamide is probably due to the modulation of post-acquisition memory processes through an action on the cholinergic basal forebrain. Our results indicate also that H3-antagonists may provide a useful approach for improving spatial recognition memory.

Topics: Animals; Basal Nucleus of Meynert; Histamine Antagonists; Male; Memory; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Recognition, Psychology

Helicobacter pylori may increase or inhibit gastric acid. We studied acid variations and plasma gastrin in cats harboring Helicobacter felis, harboring H. pylori, or free of gastric pathogens with reference to thioperamide (H(3) receptor antagonist) and SR-27417A (PAF receptor antagonist). In cats harboring H. felis, gastric mucosa were histologically normal. After H. felis eradication, pentagastrin-stimulated acid secretion was increased (40%) compared with the situation before eradication. Thioperamide abolished this inhibitory effect of H. felis, whereas SR-27417A did not. Basal and meal-stimulated plasma gastrin levels were not affected by eradication therapy. Acid secretion was inhibited (-80%) in week 3, increased from weeks 5 to 9, and remained constant for up to 42 weeks after H. pylori infection. SR-27417A had no effect on acid secretion before week 8 but inhibited it thereafter, and thioperamide increased it (20%) only before week 7 in those cats. Helicobacter inhibits gastric acid via an H(3) receptor pathway. Inflammatory mediators are thus involved in adaptation to the inhibitory effects of H. pylori on acid secretion.

Topics: Animals; Anti-Bacterial Agents; Cats; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Helicobacter; Helicobacter Infections; Helicobacter pylori; Histamine Antagonists; Kinetics; Pentagastrin; Piperidines; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Histamine H3; Thiazoles; Urease

The effect of histidine on pentylenetetrazole-induced seizures was investigated in rats.. Chemical kindling was elicited by repeated ip injection a subconvulsant dose of pentylenetetrazole (35 mg/kg) once every 48 h until the occurrence of seizure stages 4-5, and seizure activity of kindling was recorded for 30 min.. In the kindling development process, ip injection of histidine (200, 500 mg/kg), a precursor of histamine, prolonged latency for the onset of myoclonic jerks and the clonic generalized seizure, and inhibited seizure stage in a dose-dependent manner. In the kindling challenge process, histidine (500, 1000 mg/kg) and H3 antagonist thioperamide (10, 20 microg) al so showed a significant anticonvulsant effect. The inhibitory action of histidine was enhanced significantly by thioperamide (5 microg), however, was antagonized by both alpha fluoromethylhistidine (20 microg), a selective histidine decarboxylase inhibitor and H1 ant agonist pyrilamine (2, 5 mg/kg), dose-dependently and significantly. In addition, H2 antagonist zolantidine appeared no appreciable effect, even at a dose of 10 mg/kg.. These results indicated that brain endogenous histamine may play certain important role in protect against generalized clonic seizures, its action may via presynaptic H3-receptors and postsynaptic H1-receptors.

Topics: Animals; Drug Synergism; Epilepsy; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histidine; Kindling, Neurologic; Male; Pentylenetetrazole; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3

Production of N-alpha-methyl-histamine (NAMH), a histamine H(3) receptor (H3R) agonist, is reportedly promoted in Helicobacter pylori infected human gastric mucosa. NAMH was suggested to act directly on histamine H(2) receptors (H2Rs) in animals to stimulate acid secretion and to be a H2R agonist. As H2Rs and H3Rs play different roles in gastric acid secretion, it is very important to verify that NAMH is a H2R agonist.. To determine whether NAMH is a H2R agonist, as well as a H3R agonist.. We used a Chinese hamster ovary (CHO) cell line expressing human H2Rs (CHO-H2R) and control CHO cells. Expression of human H2Rs was confirmed by tiotidine binding. cAMP production in CHO-H2R and control cells in response to histamine or NAMH was measured. cAMP production in response to 10(-7) M NAMH was also measured in the presence or absence of the H2R antagonist famotidine and the H3R antagonist thioperamide.. NAMH dose dependently stimulated cAMP productions in CHO-H2R cells. This production was inhibited by famotidine but not by thioperamide. Control CHO cells were unresponsive to either histamine or NAMH. In addition, the effect of NAMH, in terms of cAMP production in CHO-H2R cells, was more potent than that of histamine-that is, with a lower EC(50) concentration and higher maximal cAMP production. Both NAMH and histamine, but not R-alpha-methyl-histamine, effectively inhibited [(3)H] tiotidine binding to CHO-H2R cells.. NAMH, which is produced in the gastric mucosa by H pylori, is a potent H2R agonist as well as a H3R agonist.

Topics: Animals; CHO Cells; Cimetidine; Cricetinae; Cyclic AMP; Famotidine; Female; Histamine Agonists; Histamine Antagonists; Histamine H2 Antagonists; Methylhistamines; Ovary; Piperidines; Receptors, Histamine H2; Receptors, Histamine H3

We tested drugs acting at histamine H3 receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)-alpha-methylhistamine (100 micromol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 micromol/kg) and antagonized by thioperamide (20 micromol/kg) or clobenpropit (20 micromol/kg). In the isolated ileum, (R)-alpha-methylhistamine (10-100 microM) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the alpha2-adrenoceptor agonist clonidine (0.1 micromol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 microM) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 micromol/kg and 1 microM, respectively). These results suggest that histamine H3 receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of a2-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.

Topics: Animals; Charcoal; Clonidine; Histamine Agonists; Histamine Antagonists; Idazoxan; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Mice; Peristalsis; Piperidines; Receptors, Adrenergic, alpha-2; Receptors, Histamine H3

It is generally believed that haloperidol exerts its motor side effects and therapeutic effects mainly by antagonizing dopamine D(2) receptors in the striatum and the nucleus accumbens, respectively. Several neurotransmitters/modulators, including glutamate, acetylcholine, adenosine and histamine, affect dopaminergic activity in these centers. We have recently shown that N-methyl-D-aspartate receptor-mediated modulation of haloperidol-induced c-fos expression differs in functionally specific regions of the striatum and the nucleus accumbens. In the present study, the entire striatum and the nucleus accumbens were comprehensively examined for the pattern of modulation of haloperidol-induced c-fos expression by adenosine A(2), histamine H(3) and muscarinic receptor antagonists. Blockade of muscarinic and H(3) receptors resulted in a profound suppression of haloperidol-induced c-fos expression in the dorsolateral part of the striatum. In addition, the H(3) receptor antagonist suppressed the effects of haloperidol in the ventrolateral aspect of the striatum and the rostral parts of the medial striatum. Muscarinic receptor antagonists suppressed haloperidol-induced c-fos expression throughout the shell and in the mid-level of the core of the nucleus accumbens while A(2) and H(3) receptor antagonists did not.We found that the muscarinic and H(3) receptor antagonists suppress the induction of c-fos by haloperidol in the dorsolateral aspect of the striatum, an area implicated in the development of extrapyramidal motor symptoms following chronic haloperidol treatment. By contrast, haloperidol-induced c-fos expression in the nucleus accumbens, an area implicated in the therapeutic effects of haloperidol, was suppressed by the muscarinic receptor antagonist, but not by the H(3) receptor antagonist. Therefore we conclude that H(3) receptor modulation may provide a useful therapeutic target in future efforts to minimize neuroleptic-induced motor side effects.

Topics: Animals; Cell Count; Cell Nucleus; Corpus Striatum; Dopamine Antagonists; Haloperidol; Histamine Antagonists; Male; Muscarinic Antagonists; Neurons; Nucleus Accumbens; Piperidines; Proto-Oncogene Proteins c-fos; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Receptors, Muscarinic; Receptors, Purinergic P1; Scopolamine; Tissue Distribution

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c-fos in the medial septum-diagonal band (MSA-DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA-DB neurons, we used the dual-probe microdialysis technique to apply drugs to the MSA-DB and record the induced effects in the projection area. Perfusion of MSA-DB with high-KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra-MSA-DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA-DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA-DB, increased the release of hippocampal ACh, whereas R-alpha-methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA-DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c-fos immunoreactivity were significantly more numerous in ciproxifan- or thioperamide-treated rats than in controls, although no colocalization of anti-c-fos and anti-ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.

Topics: Acetylcholine; Animals; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Imidazoles; Male; Microdialysis; Neurons; Perfusion; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Histamine H3; Septal Nuclei; Tetrodotoxin; Triprolidine

Drugs interfering with the histaminergic system facilitate behavioral recovery after vestibular lesion, likely by increasing histamine turnover and release. The effects of betahistine (structural analogue of histamine) on the histaminergic system were tested by quantifying messenger RNA for histidine decarboxylase (enzyme synthesizing histamine) by in situ hybridization and binding to histamine H(3) receptors (mediating, namely, histamine autoinhibition) using a histamine H(3) receptor agonist ([(3)H]N-alpha-methylhistamine) and radioautography methods. Experiments were done in brain sections of control cats (N=6) and cats treated with betahistine for 1 (N=6) or 3 (N=6) weeks. Betahistine treatment induced symmetrical changes with up-regulation of histidine decarboxylase mRNA in the tuberomammillary nucleus and reduction of [(3)H]N-alpha-methylhistamine labeling in both the tuberomammillary nucleus, the vestibular nuclei complex and nuclei of the inferior olive. These findings suggest that betahistine upregulates histamine turnover and release, very likely by blocking presynaptic histamine H(3) receptors, and induces histamine H(3) receptor downregulation. This action on the histaminergic system could explain the effectiveness of betahistine in the treatment of vertigo and vestibular disease.

Topics: Administration, Oral; Animals; Autoradiography; Betahistine; Binding Sites; Binding, Competitive; Cats; Histamine; Histamine Agonists; Histidine Decarboxylase; Hypothalamic Area, Lateral; In Situ Hybridization; Methylhistamines; Piperidines; Radioligand Assay; Receptors, Histamine H3; RNA, Messenger; Vestibule, Labyrinth

To investigate the possible involvement of histamine H(3) receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H3-receptor agonist, and thioperamide (Thiop), a selective H3-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 microg x kg(-1) x min(-1)) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 microg x kg(-1) x min(-1)) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H1-receptor antagonist) or cimetidine (a selective H2-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.

Topics: Animals; Blood Pressure; Dogs; Electric Stimulation; Electromagnetic Fields; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Histamine Agonists; Histamine Antagonists; Kidney; Male; Methylhistamines; Nerve Fibers; Norepinephrine; Piperidines; Receptors, Histamine H3; Regional Blood Flow; Renal Circulation; Sodium; Synaptic Transmission; Urodynamics

1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Calcium; Dopamine; Dopamine D2 Receptor Antagonists; gamma-Aminobutyric Acid; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Male; Membrane Potentials; Neostriatum; Piperidines; Potassium; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Histamine H3; Reserpine; Sulpiride; Thiourea

New molecular modeling tools were developed to construct a qualitative pharmacophore model for histamine H3 receptor antagonists. The program SLATE superposes ligands assuming optimum hydrogen bond geometry. One or two ligands are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible H3 antagonists. In the derived model, four hydrogen-bonding site points and two hydrophobic pockets available for binding antagonists are revealed. The model results in a better understanding of the structure-activity relationships of H3 antagonists. To validate the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and the two hydrophobic pockets simultaneously. These ligands have high H3 receptor affinity, thereby illustrating how the model can be used in the design of new classes of H3 antagonists.

Topics: Animals; Benzyl Compounds; Cerebral Cortex; Guinea Pigs; Histamine Antagonists; Histamine Release; Imidazoles; In Vitro Techniques; Intestines; Ligands; Models, Molecular; Muscle Contraction; Muscle, Smooth; Piperidines; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Receptors, Histamine H3; Software

Topics: Animals; Basal Nucleus of Meynert; Histamine Antagonists; Male; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Recognition, Psychology

The effects of an H3 agonist, R-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in the hypothalamus of rat, monkey and human brains were compared in vitro. The histamine H(3)-receptor ligands competitively inhibited MAO-B, but noncompetitively inhibited MAO-A in all three mammalian species. However, alpha-MeHA inhibited MAO-A more potently than MAO-B at high concentrations in all three species. The K(i) values for MAO-A of alpha-MeHA in hypothalamic homogenates of rat, monkey and human brains were estimated to be 1.1, 1.2 and 1.9 mM, respectively, suggesting that alpha-MeHA cannot behave as a substrate for the MAO inhibitor. In contrast, rat, monkey and human brain MAO-B activities were inhibited by thioperamide, with respective K(i) values of 174.6, 8.2 and 10.8 microM, more potently than MAO-A activity. These results indicate that thioperamide, which elicits a strong activation of histamine release and turnover to N-tele-methylhistamine from histamine, competitively inhibits the conversion of N-tele-methylhistamine to N-tele-methylimidazoleacetic acid in human and monkey brains where MAO-B predominates.

Topics: Aged; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Hypothalamus; Imidazoles; Ligands; Macaca; Methylhistamines; Middle Aged; Monoamine Oxidase; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Subcellular Fractions; Synaptic Transmission

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.

Topics: Animals; Brain; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Male; Methylhistamines; Piperidines; Pyrilamine; Ranitidine; Rats; Rats, Wistar; Receptors, Histamine H3; Sincalide; Stomach

The interaction of selective histamine H3-receptor agonist R(alpha)-methyl-histamine (RAMH) and antagonist thioperamide (THP) with some antiepileptic drugs [AED; phenytoin (PHT), carbamazepine (CBZ), sodium valproate (SVP), and gabapentin (GBP)] was studied on seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in mice. It was found that subeffective dose of THP in combination with the subeffective doses of PHT and GBP provided protection against MES and/or PTZ-induced seizures. Further, RAMH reversed the protection afforded by either PHT or GBP on MES and/or PTZ seizures. In another set of experiments, the histamine content was measured in the whole brain and in different brain regions including cerebral cortex, hypothalamus, brain stem and cerebellum following convulsant (MES and PTZ) and AED treatment. It was seen that while MES exhibited a tendency to enhance brain histamine levels, PTZ showed the opposite effect. AEDs either increased (PHT and GBP) or decreased (SVP) brain histamine content in different regions to varying degrees. The results indicate a role for histamine in seizures and in the action of AEDs and suggest that selective H3-receptor antagonists may prove to be of value as adjuncts to conventional AEDs.

Topics: Animals; Anticonvulsants; Brain; Convulsants; Drug Synergism; Epilepsy; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Receptors, Histamine H3

Several reports have indicated that, under different experimental conditions, the administration of histamine H(3)-receptor antagonists exerts procognitive effects by activating central histaminergic transmission. In the present study the action of thioperamide, a H(3)-receptor blocker, is investigated on consolidation and recall mechanisms of the rat place recognition memory. The animals have been tested on a two-trial delayed comparison paradigm in a Y-maze. Thioperamide enhances the memory retention when administered intraperitoneally (i.p.) post-acquisition (0.7 and 5.0 mg/kg are ineffective, whereas the dose of 2.0 mg/kg improves memory) but does not affect the rat performance when injected 45 min prior to the testing trial. The post-acquisition effect of thioperamide is time-dependent since the administration of the drug 30 min after the end of the training trial has no effect on memory. In addition, thioperamide reverses the amnesia induced by the post-acquisition treatment with 0.02 mg/kg i.p. of scopolamine (SCOP). The procognitive effect of thioperamide is not modified by the contemporary administration of pyrilamine, an histamine H(1)-receptor antagonist. On the contrary, the blockade of H(2)-receptors by zolantidine 10 mg/kg reverses both the effect of thioperamide alone and the drug action on the scopolamine-induced memory deficit. The results indicate that the neuronal histamine released in consequence of the post-acquisition thioperamide treatment improves place recognition memory through the activation of postsynaptic H(2)-receptors.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Histamine Antagonists; Injections, Intraperitoneal; Male; Maze Learning; Mental Recall; Orientation; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Retention, Psychology; Scopolamine

We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.

Topics: Amyloid; Animals; Anorexia; Body Weight; Calcitonin; Cholecystokinin; Eating; Histamine Antagonists; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Knockout; Pancreas; Piperidines; Receptors, Histamine H1

Effects of a chicken essence and one of its components, L-carnosine, on the hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose (2DG-hyperglycemia) in unanesthetized rats were examined. The chicken essence inhibited the 2DG-hyperglycemia. Central or peripheral administration of specific doses of L-carnosine reduced the 2DG-hyperglycemia. L-carnosine inhibited neural activities of sympathetic efferent nerves innervating the adrenal gland and liver and facilitated the activity of vagal celiac nerve innervating the pancreas in urethane anesthetized rats. Specific doses of histamine also suppressed the 2DG-hyperglycemia, and thioperamide eliminated the inhibiting actions of both histamine and L-carnosine on the 2DG-hyperglycemia. Considering mammalian muscles contain L-carnosine, these facts suggest a possibility that L-carnosine might be an endogenous control factor of the blood glucose level through autonomic nerves via H3-receptor.

Topics: Adrenal Glands; Animals; Antimetabolites; Carnosine; Celiac Plexus; Deoxyglucose; Glucose; Histamine; Histamine Antagonists; Hyperglycemia; Male; Pancreas; Piperidines; Poultry Products; Rats; Rats, Wistar; Receptors, Histamine H3

1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cells, Cultured; Cimetidine; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation; Granulation Tissue; Histamine; Histamine Antagonists; Immunohistochemistry; Indoles; Indomethacin; Inflammation; Isoquinolines; Lymphokines; Macrophages, Peritoneal; Male; Maleimides; Naphthalenes; Neovascularization, Pathologic; Piperidines; Protein Kinase C; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H2; RNA, Messenger; Specific Pathogen-Free Organisms; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Thioperamide, the prototypical histamine H(3) receptor antagonist, acts at the brain histamine H(3) autoreceptor to promote the release and metabolism of neuronal histamine, resulting in higher brain levels of the metabolite tele-methylhistamine. However, unlike thioperamide, several new histamine H(3) receptor antagonists enter the central nervous system (CNS), block brain histamine H(3) receptors and increase histamine release without increasing brain tele-methylhistamine levels. Experiments were performed presently in an attempt to understand these results. Consistent with previous findings, thioperamide significantly increased the content and synthesis rate of tele-methylhistamine in mouse and rat brain. In contrast, the histamine H(3) receptor antagonists GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and clobenpropit did not affect tele-methylhistamine synthesis rate in mouse whole brain. The histamine H(3) receptor ligand GT-2016 (5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one) had no effect on tele-methylhistamine levels in any rat brain region and decreased tele-methylhistamine synthesis rates in the mouse whole brain. To examine the possibility that these histamine H(3) receptor antagonists might prevent the methylation of newly released histamine, they were co-administered with thioperamide to determine their effects on the thioperamide-induced stimulation of tele-methylhistamine synthesis. GT-2016 significantly reduced the thioperamide-induced activation of tele-methylhistamine synthesis in mouse whole brain and in several regions of rat brain. Although further clarification is needed, these results suggest that some histamine H(3) receptor antagonists may promote the release of neuronal histamine, but also act to reduce histamine methylation in vivo by an unknown mechanism.

Topics: Analysis of Variance; Animals; Binding Sites; Brain; Histamine; Histamine Antagonists; Imidazoles; Male; Methylhistamines; Mice; Pargyline; Piperidines; Rats; Receptors, Histamine H3; Thiourea

The release of glutamate from striatal synaptosomes induced by depolarisation with 4-aminopyridine (4-AP) was studied by a method based on the fluorescent properties of the NAPDH formed by the metabolism of the neurotransmitter by glutamate dehydrogenase.Ca(2+)-dependent, depolarisation-induced glutamate release was inhibited in a concentration-dependent manner by the selective histamine H(3) agonist immepip. Best-fit estimates were: maximum inhibition 60+/-10% and IC(50) 68+/-10 nM. The effect of 300 nM immepip on depolarisation-evoked glutamate release was reversed by the selective H(3) antagonist thioperamide in a concentration-dependent manner (EC(50) 23 nM, K(i) 4 nM). In fura-2-loaded synaptosomes, the increase in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) evoked by 4-AP-induced depolarisation (resting level 167+/-14 nM; Delta[Ca(2+)](i) 88+/-15 nM) was modestly, but significantly reduced (29+/-5% inhibition) by 300 nM immepip. The action of the H(3) agonist on depolarisation-induced changes in [Ca(2+)](i) was reversed by 100 nM thioperamide. Taken together, our results indicate that histamine modulates the release of glutamate from corticostriatal nerve terminals. Inhibition of depolarisation-induced Ca(2+) entry through voltage-dependent Ca(2+) channels appears to account for the effect of H(3) receptor activation on neurotransmitter release. Modulation of glutamatergic transmission in rat striatum may have important consequences for the function of basal ganglia and therefore for the control of motor behaviour.

Topics: Animals; Corpus Striatum; Down-Regulation; Excitatory Amino Acid Antagonists; Glutamic Acid; Imidazoles; Male; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Synaptosomes

We studied the effects of histamine H(3) receptor ligands on the release of endogenous acetylcholine from the isolated, vascularly perfused rat stomach. The stomach was perfused via the celiac artery with modified Krebs-Ringer solution containing physostigmine. Released acetylcholine from the portal vein was electrochemically measured using high-performance liquid chromatography and an enzyme system. Vagus nerves were electrically stimulated twice for 2 min (0.5 or 2.5 Hz). Acetylcholine release evoked at 2.5 Hz was slightly inhibited by histamine and effectively potentiated by thioperamide, a histamine H(3) receptor antagonist. Acetylcholine release evoked at 0.5 Hz in the presence of atropine was not influenced by thioperamide, but effectively inhibited by histamine, R-alpha-methylhistamine or imetit, histamine H(3) receptor agonists. These inhibitory effects were abolished by thioperamide or pertussis toxin. These results suggest that histamine attenuates acetylcholine release from vagus nerves through histamine H(3) receptor-mediated and pertussis toxin-sensitive mechanisms in the rat stomach.

Topics: Acetylcholine; Animals; Atropine; Gastric Mucosa; GTP-Binding Proteins; Histamine; Imidazoles; Male; Methylhistamines; Perfusion; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagus Nerve; Virulence Factors, Bordetella

A series of monosubstituted benzyl analogues of the histamine H(3) receptor antagonist thioperamide were synthesized and evaluated for their histamine H(3) receptor activity on the guinea pig jejunum. Incorporation of Cl, Br, and I at the ortho position of the benzyl moiety led to an increase of the pA(2) value, whereas the same substituents at the para position led to a decrease. However, a fluorine substituent gave a strong decrease in pA(2), regardless of the position. Molecular modeling revealed a QSAR with a correlation (r = 0.93) between the pA(2) and the dihedral angle between the thiourea and the benzyl moiety and the calculated electron density on the substituted carbon atom. To verify whether this QSAR model had a predictive value, the ortho tert-butyl and methyl analogues were synthesized and evaluated. Indeed it was shown that the predicted pA(2) values of these two compounds were in accordance with the measured pA(2) values.

Topics: Benzyl Compounds; Binding Sites; Histamine Antagonists; Jejunum; Models, Molecular; Muscle Contraction; Muscle, Smooth; Piperidines; Radiopharmaceuticals; Receptors, Histamine H3; Structure-Activity Relationship

1. The modifications of hippocampal release of norepinephrine following the administration of R-(-)-alpha-methylhistamine and thioperamide, respectively agonist and antagonist of histamine H3 receptors, were assessed in freely moving rats by microdialysis. 2. Both the systemic (2 mg/kg i.p.) and local (100 microM via the probe) administration of thioperamide caused no modifications of basal release, indicating that the histaminergic system is not tonically involved in regulating the hippocampal noradrenergic activity. 3. R-(-)-alpha-methylhistamine (1 and 100 microM) produced a slight, short-lasting and dose-dependent reduction of norepinephrine release antagonized by local perfusion (100 microM) and prevented by systemic administration of thioperamide 2 mg/kg. 4. The results seem to indicate that the modulation of norepinephrine release through presynaptic H3-receptors in the rat hippocampus plays a minor role in the memory-enhancing effects of thioperamide.

Topics: Animals; Dose-Response Relationship, Drug; Hippocampus; Histamine Antagonists; Male; Memory; Methylhistamines; Norepinephrine; Piperidines; Rats; Rats, Wistar; Receptors, Histamine

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.

Topics: Animals; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Protective Agents; Receptors, Histamine H3; Seizures

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1-300 microM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H(3) receptor agonist R(-)-alpha-methylhistamine but not the selective histamine H(1) receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H(2) receptor agonist, dimaprit. The histamine H(3) receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H(1) and H(2) receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(-)-alpha-methylhistamine. The results suggest that histamine acts at presynaptic histamine H(3) receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

Topics: Animals; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Intestine, Small; Male; Methylhistamines; Norepinephrine; Phentolamine; Piperidines; Receptors, Histamine H3; Submucous Plexus; Synaptic Transmission

We investigated whether some histamine H(3)-antagonists would attenuate amygdaloid kindled seizures in rats. Thioperamide, a standard H(3)-antagonist, did not significantly reduce either seizure ranks or afterdischarge duration (ADD). Betahistine which has both H(3)-antagonistic activity and H(1)-agonistic activity significantly reduced ADD, albeit mild at a toxic dose, though seizure ranks were not affected. In addition, L-histidine, the precursor of histamine, affected neither seizure ranks, nor ADD. It was shown that H(3)-antagonists have no significant inhibitory action against amygdaloid kindled seizures, probably because released histamine was unable to inhibit those seizures.

Topics: Amygdala; Animals; Betahistine; Histamine Agonists; Histamine Antagonists; Kindling, Neurologic; Male; Piperidines; Rats; Rats, Wistar; Seizures

Topics: Acetylcholine; Amygdala; Animals; Cimetidine; Histamine Antagonists; Histamine H2 Antagonists; Male; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

The distribution of histaminergic fibers in the zebrafish brain was recently shown to resemble that in mammals. Expression of L-histidine decarboxylase (HDC) mRNA was shown only in the area corresponding to that expressing HDC in mammals. This indicates that the zebrafish could be a useful model for studies on the function of the brain histaminergic system. In this study an H(3)-like receptor is identified in zebrafish brain. With binding studies using N-alpha-[(3)H]methylhistamine on zebrafish brain sections, signals were observed in several regions. Highest densities were detected in optic tectum and hypothalamus. The autoradiographic signal was abolished completely by the H(3)-specific antagonist clobenpropit and significantly reduced by another H(3) antagonist, thioperamide. Histamine and immepip induced an increase of guanosine 5'-(gamma-[(35)S]thio)triphosphate binding in several areas of the zebrafish brain. The activation was blocked with clobenpropit but not with cimetidine or mepyramine. These results indicate that the zebrafish has a histamine H(3)-like receptor that functionally interacts with the inhibitory, G(i)/G(o), class of G proteins. No previous evidence for a histamine receptor in zebrafish exists. The receptor described here is apparently similar to the mammalian H(3) receptor, making this the first description of a histamine H(3)-like receptor in a lower vertebrate.

Topics: Animals; Autoradiography; Brain; Cimetidine; Female; Guanosine 5'-O-(3-Thiotriphosphate); Histamine Agonists; Histamine Antagonists; Imidazoles; Kinetics; Male; Methylhistamines; Piperidines; Pyrilamine; Radioligand Assay; Receptors, Histamine H3; Sulfur Radioisotopes; Thiourea; Tritium; Zebrafish

We investigated Ca(2+)/calmodulin (CaM)-mediated regulation of the desensitizing process of the histamine H(1) receptor-mediated increase in intracellular Ca(2+) concentration in human U373 MG astrocytoma cells. The desensitizing process was evaluated by measuring the histamine-induced Ca(2+) responses in cells pretreated with histamine for 15 s-30 min under various conditions. Under normal physiological conditions, desensitization developed with three successive phases : a fast desensitization within 15 s, a transient resensitization at 45 s, and a prompt and sustained redesensitization from 1 to 30 min. Similar processes of desensitization/resensitization occurred even under hypertonic conditions, where histamine-mediated internalization of the histamine H(1) receptor is inhibited. The transient resensitization phase was selectively prevented by deprivation of extracellular Ca(2+) and, even more strikingly, by the presence of W-7 (a CaM antagonist). FK506 and cyclosporin A, Ca(2+)/CaM-dependent protein phosphatase (PP2B) inhibitors, mimicked such effects. In the presence of KN-62, a Ca(2+)/CaM-dependent protein kinase II (CaM kinase II) inhibitor, the early development of desensitization disappeared, allowing a slow and simple development of desensitization. The early processes of desensitization and resensitization were unaffected by W-5, okadaic acid, and KN-04 (less potent inhibitors against CaM, PP2B, and CaM kinase II, respectively) or by GF109203X and chelerythrine (protein kinase C inhibitors). The high-affinity site for histamine was converted to a lower-affinity site by histamine treatment, which also showed a transient restoration phase at 45 s in a manner sensitive to KN-62 and FK506. These results provide the first evidence that Ca(2+)/CaM plays a crucial role in determining the early phase of the desensitizing process via activation of CaM kinase II and PP2B, by regulating agonist affinity for histamine H(1) receptors.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Astrocytoma; Calcineurin Inhibitors; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Calmodulin; Cyclosporine; Enzyme Inhibitors; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Histamine; Histamine H1 Antagonists; Humans; Kinetics; Okadaic Acid; Piperidines; Pyrilamine; Ranitidine; Receptors, Histamine H1; Sulfonamides; Tacrolimus; Tumor Cells, Cultured

The development of laser Doppler flowmetry techniques has contributed greatly to the study of cochlear blood flow (CBF). In animal models, intravenous betahistine dihydrochloride clearly increased CBF in a dose-dependent manner. This effect was greater in the cochlear vasculature than in the systemic vascular bed. The effects of betahistine were blocked by the alpha 2-antagonist idazoxan, thus suggesting an interaction between histaminergic and presynaptic adrenergic receptors. This was further supported by studies investigating the effects of electrical stimulation on CBF. Local (round window membrane) application of betahistine did not affect CBF, but had a non-specific effect on cochlear electrophysiology. This indicates that the receptors for betahistine vascular effects in the inner ear are most likely located in the modiolar artery. More recently, laser Doppler flowmetry techniques have been applied to human subjects. It has been shown that intratympanic application of adrenaline affects CBF and that this blood flow is under vigorous sympathetic control. Electrical stimulation has also been used to obtain measures of dynamic responsiveness in human subjects. This results in an increase in CBF, which is dependent on the intensity of the stimulation. Preliminary evidence indicates that this procedure can provide a standardized measure of the dynamic properties of CBF and may provide a means to differentially identify patients with compromised vasculature.

Topics: Adrenergic Agonists; Adrenergic alpha-Antagonists; Animals; Betahistine; Blood Flow Velocity; Cochlea; Dose-Response Relationship, Drug; Electric Stimulation; Epinephrine; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Humans; Idazoxan; Laser-Doppler Flowmetry; Microcirculation; Piperidines; Vasodilator Agents

Recently cDNA encoding the histamine H3 receptor was isolated after 15 years of considerable research. However, several studies have proposed heterogeneity of the H3 receptor. We report here the molecular cloning and characterization of a novel type of histamine receptor. A novel orphan G-protein-coupled receptor named GPRv53 was obtained through a search of the human genomic DNA data base and analyzed by rapid amplification of cDNA ends (RACE). GPRv53 possessed the features of biologic amine receptors and had the highest homology with H3 receptor among known G-protein-coupled receptors. Mammalian cells expressing GPRv53 were demonstrated to bind and respond to histamine in a concentration-dependent manner. In functional assays, not only an H3 receptor agonist, R-(alpha)-methylhistamine, but also a H3 receptor antagonist, clobenpropit, and a neuroleptic, clozapine, activated GPRv53-expressing cells. Tissue distribution analysis revealed that expression of GPRv53 is localized in the peripheral blood leukocytes, spleen, thymus, and colon, which was totally different from the H3 receptor, whose expression was restricted to the brain. The discovery of the GPRv53 receptor will open a new phase of research on the physiological role of histamine.

Topics: Amino Acid Sequence; Cell Line; Cloning, Molecular; Colon; Histamine; Humans; Leukocytes; Molecular Sequence Data; Piperidines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Sequence Alignment; Sequence Homology, Amino Acid; Spleen; Thymus Gland

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.

Topics: Animals; Apomorphine; Chlorpheniramine; Dimaprit; Diphenhydramine; Dopamine Agonists; Drug Interactions; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Thiourea; Toluidines

Starting from the sequence of the human histamine H(3) receptor (hH(3)R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)alpha-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H(3) receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH(3)R located in the vicinity of Asp(114) purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H(3)R in the two species.

Topics: Amino Acid Sequence; Amino Acid Substitution; Amino Acids; Animals; Binding, Competitive; COS Cells; DNA, Complementary; Dose-Response Relationship, Drug; Histamine Antagonists; Humans; Imidazoles; Membrane Proteins; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Piperidines; Protein Structure, Tertiary; Radioligand Assay; Rats; Receptors, Histamine H3; Sequence Alignment; Sequence Homology, Amino Acid; Tritium

Experimental anxiety in mice was evaluated using a light/dark test at 60 min after injection of various histaminergics. Thioperamide, a histamine H(3) receptor inhibitor (5-20 mg/kg, intraperitoneal [IP]), Compound 48/80, a mast cell degranulator (0.1-10 microg/2 microl, intracerebroventricularly [ICV]), mepyramine, a histamine H(1) receptor antagonist (0.1-10 microg/2 microl, ICV) or cimetidine, a histamine H(2) receptor antagonist (0.1-10 microg/2 microl, ICV) alone did not affect the locomotive activity, the time spent in the light zone, and number of shuttle crossings in the light/dark test. However, the time spent in the light zone and the number of shuttle crossings significantly decreased only when cimetidine (0.1-10 microg/2 microl, ICV) was co-treated with either thioperamide (10 mg/10 ml/kg, IP) or Compound 48/80 (1.0 microg/2 microl, ICV). The decrease in these behavioral parameters suggests induced experimental anxiety in mice. The experimental anxiety was antagonized by mepyramine (10 microg/2 microl, ICV). These results suggest that not only neuronal histamine release induced by thioperamide but also non-neuronal (mast cells) histamine release induced by Compound 48/80 play an important role in inducing experimental anxiety via post-synaptic H(1) and H(2) receptors. In addition, it is likely that the anxiety may be mediated by the stimulation of H(1) receptors, while H(2) receptors may inhibit the anxiety produced by the activation of H(1) receptors.

Topics: Animals; Anxiety; Cimetidine; Disease Models, Animal; Histamine Antagonists; Histamine Release; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; p-Methoxy-N-methylphenethylamine; Piperidines; Pyrilamine

To investigate whether or not histamine was involved in scopolamine-induced spatial memory deficits evaluated in 8-arm radial maze performance of rats.. Eight-Arm radial maze performance was used to measure spatial memory in rats, and the brain regions were subsequently dissected and histamine contents were determined by HPLC.. Intracerebroventricular (icv) injection of histamine (100 or 200 ng) or thioperamide (50 micrograms), and intraperitoneal (i.p.) injection of histidine (1000 mg/kg) ameliorated memory impairment induced by scopolamine regarding both parameters of radial maze performance. 2-Thiazolylethylamine, but not 4-methylhistamine showed the similar effect to histamine. Both histamine (200 ng, icv) and histidine (1000 mg/kg, i.p.) were equally effective in increasing the histamine content in the cortex, hippocampus, and hypothalamus.. These results suggest that brain histamine plays an important role in learning and memory, and its action may be due to cholinergic neurons.

Topics: Animals; Brain; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Wistar; Scopolamine; Thiazoles

The effect of stress- or lipopolysaccharide (LPS) endotoxin-induced release of ACTH, beta-endorphin (beta-END) and prolactin (PRL) was investigated in two groups of conscious male rats: (1) Rats pretreated with different H3 receptor agonists, which inhibit neuronal histamine (HA) synthesis and release, and (2) rats with bilateral posterior hypothalamic lesion, which destroys the histaminergic perikarya exclusively localized in the mammillary nuclei. The H3 receptor agonists R(alpha)methyl-HA, BP 2-94 or imetit injected intraperitoneally (ip) had no effect on basal secretion of ACTH or PRL but inhibited the ACTH and PRL responses to restraint stress and the ACTH response to LPS endotoxin. LPS had no effect on PRL secretion. The inhibitory effect of the agonists was prevented by prior ip administration of the H3 receptor antagonist thioperamide. Bilateral lesion of the posterior hypothalamus inhibited the ACTH, beta-END and PRL responses to restraint stress, ether stress and LPS endotoxin, whereas sham operation had no effect compared to nonoperated control rats. In addition, posterior hypothalamic lesion inhibited the PRL response but not the ACTH and beta-END responses to activation of serotonergic neurons induced by ip administration of the 5-HT precusor 5-hydroxytryptophan in combination with the 5-HT re-uptake inhibitor fluoxetine. Thus, serotonergic pathways were not damaged by the lesions. The present results support our previous findings that inhibition of neuronal HA synthesis by alpha-fluoromethylhistidine as well as blockade of H1 or H2 receptors inhibit the ACTH, beta-END and PRL responses to stress and LPS endotoxin and further substantiate an important role of histaminergic neurons in the mediation of the stress-induced release of pituitary stress hormones. Furthermore, in accordance with our previous findings, the lesion experiments indicated the existence of an interaction between the histaminergic and serotonergic system in regulation of the stress- and LPS-induced PRL release.

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Fluoxetine; Histamine; Histamine Agonists; Histamine Antagonists; Hypothalamus, Posterior; Lipopolysaccharides; Male; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Rats, Wistar; Receptors, Histamine H3; Restraint, Physical; Selective Serotonin Reuptake Inhibitors; Stress, Physiological

Stimulation-evoked 3H-noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3 receptor-mediated inhibition of noradrenaline release in human brain.

Topics: Animals; Brain; Cerebral Cortex; Dimethindene; Electric Stimulation; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; Male; Mice; Mice, Inbred Strains; Norepinephrine; Piperidines; Ranitidine; Receptors, Histamine H3; Thiourea; Tritium

Studies were performed to assess the functional activity of histamine H3 receptors on neurogenic sympathetic end organ responses in cryopreserved human saphenous vein. (R)-alpha-methylhistamine inhibited electrical field stimulation-evoked contractile responses in a dose dependent manner (pD2 = 8.20). Prazosin (1 microM) and tetrodotoxin (1 microM) blocked the electrical field stimulation-evoked contractile responses in human saphenous vein indicating a sympathetic neural origin of these contractions. The histamine H3 antagonists thioperamide (pA2 = 8.41) and clobenpropit (pA2 = 10.10) produced parallel rightward shifts in the concentration response curve to (R)-alpha-methylhistamine in human saphenous vein and guinea pig ileum (pA2 = 8.59 and 9.83, respectively). Pretreatment with (R)-alpha-methylhistamine (1 microM) did not alter contractions to exogenous norepinephrine in human saphenous vein. In addition, clonidine (pD2 = 10.28) inhibited electrical field stimulation-evoked contractile responses in human saphenous vein which were blocked by yohimbine (30 nM, pA2 = 9.92) but did not alter the (R)-alpha-methylhistamine dose response curve. These results demonstrate the presence of functional presynaptic histamine H3 heteroreceptors on cryopreserved human saphenous vein sympathetic nerves that, upon activation, attenuate electrical field stimulation-evoked contractile responses in this vessel.

Topics: Adrenergic alpha-Antagonists; Aged; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Female; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Humans; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Middle Aged; Muscle Contraction; Piperidines; Prazosin; Receptors, Histamine H3; Saphenous Vein; Tetrodotoxin; Thiourea; Yohimbine

Betahistine is used for treatment of several vestibular disorders. Despite the accepted use of this histamine-like substance, its mechanism of action is not well understood. The purpose of this study was to assess the possibility that one of the activities of betahistine is increasing blood flow in the peripheral vestibular end organs. Using a novel surgical approach, we identified the posterior semicircular canal ampulla of guinea pigs and placed a laser Doppler probe in position to obtain blood flow measurements from the posterior semicircular canal ampulla. Blood pressure, heart rate, and vestibular blood flow were continuously recorded. Concentration-response curves were obtained for betahistine (2.5, 5, 7.5, and 10 mg/kg) and control-vehicle (0.15 mol/L NaCl) infusions. A separate group of subjects was pretreated with the competitive selective H3 agonist, thioperimide maleate, before betahistine treatment. Increases in vestibular blood flow and decreases in blood pressure were observed in response to betahistine infusions. Pretreatment with thioperamide maleate abolished these changes at low doses of betahistine and attenuated the responses at higher doses of betahistine. These results show that betahistine administration induces increases in vestibular blood flow. These findings support the potential use of betahistine for treatment of vestibular disorders, which may be caused by compromised circulation.

Topics: Animals; Betahistine; Blood Flow Velocity; Blood Pressure; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Infusions, Intravenous; Laser-Doppler Flowmetry; Male; Piperidines; Time Factors; Vasodilator Agents; Vestibule, Labyrinth

1. Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro. 2. Application of histamine (10 microM, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 microM). 3. The magnitude of the depression caused by histamine was inversely related to the extracellular Ca2+ concentration. Application of the N-type calcium channel blocker omega-conotoxin (0. 5 or 1 microM) or the P/Q-type calcium channel blocker omega-agatoxin (800 nM) did not prevent depression of synaptic transmission by histamine. 4. The potassium channel blocker 4-aminopyridine (4-AP, 100 microM) enhanced synaptic transmission and reduced the depressant effect of histamine (10 microM). 4-AP reduced the effect of histamine more in 2 mM extracellular calcium than in 4 mM extracellular calcium. 5. Histamine (10 microM) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency. 6. Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 microM), or by an inhibitor of tyrosine kinases, Lavendustin A (10 microM). 7. Application of adenosine (20 microM) or the adenosine A1 agonist N6-cyclopentyladenosine (CPA, 0.3 microM) completely occluded the effect of histamine (10 microM). 8. We conclude that histamine, acting on histamine H3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry, via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H3 receptors and adenosine A1 receptors act upon a common final effector to cause presynaptic inhibition.

Topics: 4-Aminopyridine; Adenosine; Animals; Calcium Channel Blockers; Dentate Gyrus; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Glutamic Acid; Histamine; Histamine Antagonists; In Vitro Techniques; Male; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Protein Kinase Inhibitors; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Histamine H3; Synaptic Transmission

Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known.. We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats.. PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY.. These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.

Topics: Analysis of Variance; Animals; Appetite Regulation; Bulimia; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Fasting; Histamine Antagonists; Hyperphagia; Injections, Intraventricular; Male; Peptide YY; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Satiation; Time Factors

Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R-alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied.

Topics: Analysis of Variance; Animals; Anxiety; Depression; Disease Models, Animal; Histamine Agonists; Histamine Antagonists; Imidazoles; Ligands; Male; Maze Learning; Methylhistamines; Mice; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Swimming; Thiourea

Histamine is one of the neurotransmitters suppressing appetite, but the interactions of histaminergic neurons with other neurons in satiety centers have not been clarified. Noradrenaline in the para-ventricular nucleus (PVN) has been shown to stimulate feeding. This study was designed to determine whether histamine modulates noradrenaline release via histamine H1-receptors in the PVN. Freely-fed rats were i.c.v. injected with an histamine H1-receptor antagonist, triprolidine (82 microg), and/or an alpha 2-adrenoceptor antagonist, rauwolscine (0, 20 and 40 microg), and food intake (n=8 each) over 2 h was measured. Food intake was significantly (p<0.01) increased in rats injected with triprolidine alone. The triprolidine-elicited increase in food intake was suppressed by rauwolscine at a dose of 40 microg. The noradrenaline content in perfusates collected by a microdialysis probe aimed at the PVN was significantly (p<0.05) increased by the presence of triprolidine in the perfusates. The noradrenaline concentrations in perfusates collected from the PVN were elevated after tyramine (a noradrenaline uptake inhibitor) administration, but not when both tyramine and histamine were given. In conclusion, these results suggest that histamine inhibits noradrenaline release from hypothalamic nerve terminals in the PVN, and thus suppresses feeding behavior.

Topics: Adrenergic alpha-Antagonists; Animals; Eating; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Injections, Intraventricular; Male; Microdialysis; Norepinephrine; Paraventricular Hypothalamic Nucleus; Piperidines; Rats; Rats, Wistar; Triprolidine; Yohimbine

Topics: Acetylcholine; Animals; Cimetidine; Hippocampus; Histamine Antagonists; Histamine H2 Antagonists; Male; Piperidines; Rats; Rats, Wistar

The aim of the present experiments was to test the role played by the interaction of the selective H3 receptor antagonist, thioperamide, with the cholinergic, histaminergic, and serotonergic systems in modifying memory. The behavioral tests used (open-field and passive-avoidance repetition) were selected on the basis of the action displayed by thioperamide in these behavioral situations. Posttrial administration of thioperamide (5 mg/kg) resulted in an improvement in memory consolidation, as tested in the repetition of the open-field test, but repeated posttrial administration of thioperamide (2 or 5 mg/kg) had no effect in the repetition of passive avoidance test. Scopolamine (2 mg/kg) caused a deterioration in the memory processes in both tests: this effect was blocked by 2 mg/kg of thioperamide, which was itself ineffective in the test. These results may suggest that both the improvement in memory due to thioperamide and its antagonism of the amnestic effects of scopolamine are determined by activation of central cholinergic systems, due to thioperamide inhibition of H3 heteroreceptors. Diphenhydramine (2 or 10 mg/kg) was itself ineffective in the tests, but counteracted the memory improvement caused by thioperamide in the repetition of the open-field test. The effect of diphenhydramine is discussed in terms of interactions between histaminergic and cholinergic systems. Methysergide counteracted the effect of thioperamide in the open-field test only at a high dosage (50 mg/kg). The possible implication of serotonergic systems on the effects of the methysergide-thioperamide interaction in the memory process is discussed.

Topics: Animals; Avoidance Learning; Diphenhydramine; Drug Interactions; Exploratory Behavior; Histamine Antagonists; Male; Memory; Methysergide; Mice; Muscarinic Antagonists; Piperidines; Scopolamine; Serotonin Antagonists

The activation of presynaptic histamine 3 (H(3)) receptors inhibits the release of histamine and other neurotransmitters from central nervous system neurons. Rat brain mast cells (MCs) release histamine and 5-hydroxytryptamine (5-HT) in response to neuropeptides and neurotransmitters secreted from adjacent neurons. Dura MCs also degranulate in response to antidromic trigeminal nerve stimulation and with acute psychological stress. Such findings have implicated brain MCs in certain neuroinflammatory disorders, such as migraines. We investigated the ultrastructural appearance of control and stimulated thalamic/hypothalamic (brain) MCs before and after treatment with the H(3) receptor agonist N(alpha)-methylhistamine (N(alpha)-mH) and the H(3) receptor antagonist thioperamide (Th). Ultrastructural investigation of brain MCs stimulated with compound 48/80 revealed extensive intragranular changes that paralleled 5-HT secretion but without degranulation by exocytosis typical of connective tissue MCs. N(alpha)-mH significantly reduced these morphological changes, as well as 5-HT release from brain MCs and neurons stimulated with KCl; conversely, Th augmented both histamine and 5-HT release from brain neurons and MCs. Neither N(alpha)-mH nor Th had any effect on peritoneal MCs. Simultaneous addition of both drugs largely antagonized each other's effects on brain MC activation and 5-HT secretion. Ultrastructural observations and lack of lactic dehydrogenase release in the perfusate excluded any cytotoxic effect. The ability of H(3) agonists to inhibit brain MC activation, as well as secretion of 5-HT from both brain MCs and neurons, may be useful in the management of migraines.

Topics: Animals; Brain; Cell Survival; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Mast Cells; Methylhistamines; Neurons; Peritoneal Cavity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Serotonin

Characterization of the histamine H3 receptor in rodent species has been extensive but limited characterization has been done with primate or human tissue. We have characterized the binding of [3H]Nalpha-methylhistamine to cynomolgus monkey and human brain membranes to determine whether there are any significant differences among species' pharmacology. In monkey, [3H]Nalpha-methylhistamine bound, in a guanine nucleotide-sensitive fashion, to an apparently homogeneous class of sites at equilibrium (K(D) = 1.4 nM, Bmax = 34 fmol/mg protein). The profile of binding was broadly similar to that of rodents, with a couple of significant differences. Most notably, the potency of the histamine H3-receptor-specific antagonist thioperamide (Ki = 240 nM) was substantially less than reported for rodents and under assay conditions that yield a two-site curve fit in rodents only a single class of thioperamide binding sites was detected in monkey. Burimamide, however, yielded a two-site curve fit (KiH = 6.7 nM, KiL = 1100 nM) independent of the presence of sodium in the assay, as it does in rodents. Characterization of the human brain histamine H3 receptor showed that it was similar to the monkey and not rodent receptor. Our findings indicate that differences between primate and rodent histamine H3 receptors of potentially serious importance for the discovery of antagonists active in humans do exist.

Topics: Animals; Brain; Burimamide; Cell Membrane; Guanine Nucleotides; Humans; In Vitro Techniques; Macaca fascicularis; Methylhistamines; Piperidines; Receptors, Histamine; Species Specificity

The effects of histamine and other inflammatory mediators on the electrophysiology and intracellular free calcium ([Ca(2+)](i)) of human oviductal epithelial cells, grown as a polarized layer in primary culture, were studied. Transepithelial potential difference (PD) and short-circuit current (I(scc)) were recorded using a modified Ussing chamber. Resistance (R) was calculated from the measurements of PD and I(scc). Basally applied histamine produced transient increases in PD and I(scc) with a small decrease in R. The histamine effect was reduced by triprolidine (H(1) receptor antagonist) but was unaffected by H(2) (ranitidine) or H(3) (thioperamide) receptor antagonists. Blockers of Na(+), K(+), or Na(+)/K(+)/2Cl(-) channels did not affect histamine action. Blockers of Cl(-)/HCO(3)(-) channels or Ca(2+) channels reduced the histamine effect. Platelet activating factor (PAF), applied apically, increased PD and I(scc). Histamine produced a transient increase in fluorescence of Fura 2-AM dye, indicating an increase in [Ca(2+)](i). Triprolidine pretreatment inhibited histamine-stimulated [Ca(2+)](i) increase. Cimetidine, (H(2) receptor antagonist), ranitidine, or thioperamide reduced the histamine effect. Histamine increased contractions of both circular and longitudinal smooth muscles in oviduct segments, an effect that was antagonized by triprolidine or thioperamide but not by ranitidine. Histamine's action on Ca(2+) and Cl(-) movements may adversely affect oviductal fluid production and decrease fertility. PAF's effects on Cl(-) movements may be important for normal embryo transport.

Topics: Alprostadil; Calcium; Cells, Cultured; Chlorides; Dinoprostone; Electric Conductivity; Electrophysiology; Epithelial Cells; Fallopian Tubes; Female; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Ion Channels; Leukotriene B4; Membrane Potentials; Piperidines; Platelet Activating Factor

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whether pretreatment with H1, H2, H3 receptor blockers, and cyclooxygenase and leukotriene pathway inhibitors was useful in preventing the depression in left ventricular (LV) contractility known to occur in this model. The dose of allergen was varied to produce similar degrees of shock between treatments. The animals were studied under pentobarbital anesthesia in which the treatment studies were approximately 3 wk apart. LV volumes were measured by sonomicrometric techniques. During challenge, mean arterial blood pressure (Pa), cardiac output (Q), and LV end-diastolic pressure (LVEDP) decreased approximately 50% compared with preshock values in all treatments. Histamine H3 receptor blockade was associated with higher heart rates (HR) and higher stroke work (SW) (p < 0.05) as compared with the other treatment studies. We conclude that histamine H3 activation by inhibiting adrenergic neural norepinephrine release contributes to cardiovascular collapse in AS.

Topics: Anaphylaxis; Animals; Chlorpheniramine; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Leukotrienes; Lipoxygenase Inhibitors; Myocardial Contraction; Piperidines; Prostaglandins; Quinolines; Ranitidine; Receptors, Histamine H3; Stroke Volume; Ventricular Function, Left

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins (prost), and leukotrienes (leuk) on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear.. In randomized design, we investigated whether blockade of histamine H1, H2, and H3 receptors or inhibition of the cyclooxygenase (cyclo) and lipoxygenase pathways (lipox) prevented AS in ragweed sensitized dogs. Seven dogs were studied under pentobarbital anesthesia in which the treatment studies were approximately 2 weeks apart.. During H1 receptor blockade, the decreases in blood pressure and cardiac output otherwise observed in AS were attenuated (P < 0.05) and the release of prost, thromboxanes, and leuk were reduced as compared with nontreatment studies. Cyclo inhibition also attenuated cardiovascular collapse and mediator release in AS, but the other treatments showed no effects.. H1 receptor blockade and cyclo may attenuate cardiovascular shock in AS. These agents inhibit autacoid release from mast cells in addition to any specific receptor blocking and pathway inhibition effects.

Topics: Analysis of Variance; Anaphylaxis; Animals; Cardiovascular System; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Inflammation Mediators; Lipoxygenase Inhibitors; Piperidines; Quinolines; Random Allocation; Ranitidine; Receptors, Histamine H3

1 We have investigated the binding of a novel histamine H3-receptor antagonist radioligand, [3H]- clobenpropit ([3H]-VUF9153), to guinea-pig cerebral cortex membranes. 2 Saturation isotherms for [3H]-clobenpropit appeared biphasic. Scatchard plots were curvilinear and Hill plot slopes were significantly less than unity (0.63+/-0.03; n = 12+/-s.e.mean). The radioligand appeared to label two sites in guinea-pig cerebral cortex membranes with apparent affinities (pKD') of 10.91+/-0.12 (Bmax = 5.34+/-0.85 fmol mg(-1) original wet weight) and 9.17+/-0.16 (Bmax = 23.20+/-6.70 fmol mg(-1)). 3 In the presence of metyrapone (3 mM) or sodium chloride (100 mM), [3H]-clobenpropit appeared to label a homogeneous receptor population (Bmax=3.41+/-0.46 fmol mg-1 and 3.49+/-0.44 fmol mg(-1), pKD' = 10.59+/-0.17 and 10.77+/-0.02, respectively). Scatchard plots were linear and Hill slopes were not significantly different from unity (0.91+/-0.04 and 0.99+/-0.02, respectively). Granisetron (1 microM), rilmenidine (3 microM), idazoxan (0.3 microM), pentazocine (3 microM) and 1,3-di-(2-tolyl)guanidine (0.3 microM) had no effect on the binding of [3H]-clobenpropit. 4 The specific binding of [3H]-clobenpropit appeared to reach equilibrium after 25 min at 21+/-3 degrees C and remained constant for >180 min. The estimated pKD' (10.27+/-0.27; n = 3+/-s.e.mean) was not significantly different from that estimated by saturation analysis in the presence of metyrapone. 5 A series of histamine H3-receptor ligands expressed affinity values for sites labelled with [3H]-clobenpropit which were not significantly different from those estimated when [3H]-R-alpha-MH was used to label histamine H3-receptors in guinea-pig cerebral cortex membranes.

Topics: Animals; Binding, Competitive; Cerebral Cortex; Guinea Pigs; Histamine Antagonists; Imidazoles; In Vitro Techniques; Kinetics; Metyrapone; Piperidines; Radioligand Assay; Receptors, Histamine H3; Thiourea; Tritium

1. We have investigated the effects of inflammatory mediators on visceral afferent discharge and afferent responses to bradykinin (BK) in rat jejunum using a novel in vitro technique. 2. Prostaglandin E2 (1 microM) augmented responses to BK without affecting basal firing, while histamine (100 microM) and adenosine (100 microM) activated basal discharge and enhanced BK responses. In contrast, 5-HT (100 microM) increased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H1 (pyrilamine) and H3 (thioperamide) but not H2 (ranitidine) receptor antagonists at 10 microM. In contrast, sensitization to BK induced by histamine was inhibited by ranitidine (10 microM). 4. Afferent discharge induced by adenosine was blocked by the A1 receptor antagonist DPCPX (10 microM) but remained unaffected by A2A receptor blockade with ZM241385 (10 microM). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induced responses were unaffected by the A3 receptor agonist IB-MECA (1 microM). While involvement of A2B receptors is not excluded, adenosine may activate afferent discharge through A1 receptors, while sensitization to BK could involve a receptor other than A1, A2A or A3, possibly the A2B receptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 microM) prevented sensitization after histamine but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred without changes in basal firing and was unaffected by naproxen. 7. In conclusion, afferent discharge induced by BK is augmented by histamine, adenosine and PGE2, but not by 5-HT. Evidence suggests that sensitization involves separate mechanisms from afferent activation. Sensitization may be mediated by increases in cAMP following direct activation by mediators at the nerve terminal or through indirect pathways such as the release of prostaglandins.

Topics: Adenosine; Animals; Bradykinin; Bucladesine; Cyclooxygenase Inhibitors; Dinoprostone; Histamine; Histamine Antagonists; Histamine H2 Antagonists; In Vitro Techniques; Jejunum; Male; Membrane Potentials; Naproxen; Neurons, Afferent; Piperidines; Ranitidine; Rats; Rats, Inbred Strains; Serotonin; Stimulation, Chemical; Triazines; Triazoles; Xanthines

The mnemonic performances of male and female rats were compared in an object recognition test. Females were still able to recognize a previously identified object after a 90-min between-trial interval, compared with only 60 min in the males. Because histamine (HA) involvement in memory processes has been strongly suggested, the effect of H3-HA autoreceptor antagonist thioperamide was investigated. This drug was found to produce a dose-dependent promnestic effect in both sexes, but it did not influence the time course of memory retrieval. These behavioral data were compared to the density of H1-HA, H2-HA, and H3-HA receptors in cortical membranes. The densities of H1-HA and H2-HA receptors were greater in the females, whereas that of H3-HA was substantially the same in both sexes. The behavioral effect of thioperamide was very similar in both sexes, and this agrees with a similar H3-HA receptor density; however a better memory performance might have been expected in the female after thioperamide treatment (in view of different H1-HA and H2-HA receptor density), but this was not found. Because thioperamide has also been demonstrated to influence the acetylcholine release, its possible role in regulating the cholinergic memory effect was investigated. The scopolamine-reduced visual retrieval was antagonized by thioperamide in a similar way in both sexes. In conclusion, these data have shown a better performance of the female in a visual memory test, but this behavioral difference could not be affected by an H3-HA receptor-dependent manipulation of histaminergic and cholinergic systems.

Topics: Animals; Drug Interactions; Female; Histamine Antagonists; Histamine Release; Male; Memory; Muscarinic Antagonists; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Sex Characteristics

Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine.. To determine the direct effects of histamine receptor agonists on isolated gastrin cells.. Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates.. NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01).. NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia.

Topics: Animals; Antibodies, Monoclonal; Cells, Cultured; Chlorpheniramine; Dimaprit; Dose-Response Relationship, Drug; Drug Interactions; Gastrin-Secreting Cells; Gastrins; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H2 Antagonists; Piperidines; Pyloric Antrum; Rabbits; Ranitidine; Receptors, Histamine

To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with alpha-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion with the H3 receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H3 agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H3 receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566. The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H3 receptor agonists imetit and immepip is due to stimulation of H3 heteroreceptors, while the increase of acetylcholine release by the H3 receptor antagonist thioperamide is elicited via blockade of H3 autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.

Topics: Acetylcholine; Animals; Bicuculline; Dopamine; Dopamine Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Histamine; Histamine Antagonists; Ligands; Male; Methylhistidines; Neurons; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Stereotaxic Techniques; Time Factors; Visual Cortex

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by supraspinally administered mu-epsilon-, delta-, and kappa-opioid receptor agonists. The effects of intrathecal (i.t.) injections with cyproheptadine [a histamine-1 (H1) receptor antagonist], ranitidine (a H2 receptor antagonist), or thioperamide (a H3 receptor antagonist) injected i.t., on the antinociception induced by morphine (a mu-receptor antagonist), beta-endorphin (an epsilon-receptor agonist), D-Pen(2,5)-enkephalin (DPDPE, a delta-receptor agonist) or trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohxyl] benzeocetamide (U50,488H, a kappa-receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (from 0.31 to 62 nmole), ranitidine (from 0.28 to 56 nmole), or thioperamide (from 0.24 to 48 nmole) alone did not show any antinociceptive effect. The i.t. pretreatment with cyproheptadine or thioperamide dose-dependently attenuated the inhibition of the tail-flick response induced by i.c.v. administered morphine (0.6 nmole), b-endorphin (0.03 nmole), DPDPE (1.5 nmole), and U50,488H (130 nmole). In addition, the i.t. pretreatment with ranitidine dose-dependently attenuated the inhibition of the tail-flick response induced by morphine, b-endorphin and U50,488H without affecting DPDPE-induced response. Our results suggest that spinal histamine H1 and H3 receptors may involved in the production of antinociception induced by supraspinally applied morphine, b-endorphin, DPDPE and U50,488H. Spinal H2 receptors appear to be involved in supraspinally administered morphine, b-endorphin- and U50,488H-induced antinociception but not DPDPE-induced antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cerebral Ventricles; Cyproheptadine; Enkephalin, D-Penicillamine (2,5)-; Histamine Antagonists; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Pain; Piperidines; Ranitidine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Receptors, Opioid; Spinal Cord

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cognition; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Methylhistamines; Pattern Recognition, Visual; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Thiourea

Metoprine elevates brain histamine content by blocking the conversion of histamine to methylhistamine. It suppresses food intake, increases water intake. and induces diuresis in rats. In the present experiment, to study which receptors were involved in these metoprine-induced changes, H1, H2, and H3 receptor blockers were administered to metoprine (10 mg/kg IP)-treated rats. The food and water consumption and urine excretion were measured at 10 and 24 h after the drug administration. It was found that systemic administration of the H3 receptor antagonist, thioperamide (5 mg/kg IP), supplemented the feeding suppressive effect of metoprine. In addition to this, the H1 receptor antagonist mepyramine (20 mg/kg IP) antagonized the suppression of feeding in metoprine-treated rats, whereas the H2 receptor antagonist, ranitidine (100 mg/kg IP), had no effect. Mepyramine also decreased the diuretic response to metoprine, whereas ranitidine or thioperamide were virtually without effect. The present results show that elevation of brain histamine content by inhibiting the catabolism of histamine suppresses food intake, and this effect of metoprine can be abolished by pretreatment with antihistamines. Although the blockade of H1 receptors also attenuates the diuretic response to metoprine, further studies are needed to understand the mechanisms that mediate the effects of metoprine on water balance.

Topics: Animals; Brain Chemistry; Diuresis; Enzyme Inhibitors; Feeding Behavior; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Piperidines; Pyrilamine; Pyrimethamine; Ranitidine; Rats; Rats, Wistar; Water-Electrolyte Balance

The aim of this study was to investigate the mechanism and site of action of betahistine dihydrochloride in the inner ear of the guinea pig. Betahistine-evoked increases in cochlear blood flow (CBF) have been presumed to be due to the drug effect on the later wall capillary bed or larger feeding vessels in the cochlea vascular system. As such, the mechanism of action could be due to inhibition of H3 receptors. Betahistine may also have a direct effect on postsynaptic H1/H2 receptors and/or an effect modulated by other autonomic receptors. Betahistine-evoked CBF responses were assessed by laser Doppler flowmetry in the presence of an H3 agonist (alpha N-methyl-histamine dihydrochloride), an H3 antagonist (thioperamide), an H2 antagonist (cimetidine) or an alpha 2 antagonist (idazoxan). The effects of betahistine on circulation in the anterior inferior cerebellar artery (AICA) and ipsilateral stria vascularis (SV) were assessed using intravital microscopy (IVM). Findings showed that betahistine increased CBF and reduced systemic blood pressure (BP). In contrast, alpha N-methylhistamine dihydrochloride had no effect on baseline CBF or BP and did not influence betahistine-induced increases in CBF. Thioperamide reversed the effects of betahistine on CBF, but had no effect on baseline CBF or BP. Cimetidine had no marked effect on baseline CBF or betahistine-induced increases in CBF Idazoxan had no consistent effects on baseline CBF, but abolished the effect of betahistine on CBF. The mean increase of red blood cell velocity in SV capillaries was 15% and occurred without a demonstrable change in capillary diameters. In contrast, the diameter of the AICA increased by 17-20%, indicating that betahistine-evoked increases in CBF resulted primarily from vasodilatation of the AICA. We suggest that this effect may be mediated via presynaptic H3 heteroreceptors and autonomic alpha 2 receptors.

Topics: Animals; Betahistine; Cimetidine; Cochlea; Ear, Inner; Female; Guinea Pigs; Histamine Antagonists; Idazoxan; Male; Methylhistamines; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Vasodilator Agents

High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Albuterol; Asthma; Bronchoalveolar Lavage Fluid; Clone Cells; Cyclic AMP; Dinoprostone; Enzyme Activation; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Impromidine; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Lung; Methylhistamines; Piperidines; Pyridines; Ranitidine; T-Lymphocytes; Triprolidine

We assessed the functional role of the histamine H3-receptor in conscious intact rats during activation of the sympathoadrenal axis.. Male Sprague-Dawley rats, with or without cerebroventricular cannula, were subjected to mild footshocks and mean arterial pressure (MAP) and heart rate were determined using a tail-cuff plethysmograph.. Saline, phentolamine (3 mg/kg, i.p.), (R)-alphafluoromethylhistidine (AFMH) (100 mg/kg, i.p., or 100 microg/5 microl, i.v.t.), (R)-alphamethylhistamine (AMH) (2 mg/kg, i.p. or 100 microg/5 microl, i.v.t.), thioperamide (THIO) (1 or 2 mg/kg, i.p., or 100 microg/5 microl, i.v.t.), mepyramine (10 mg/kg, i.p.), cimetidine (2 mg/kg, i.p.).. Urinary catecholamines were determined by fluorometry. Statistical differences between experimental groups were evaluated by Student's t-test or one-way ANOVA.. Footshocks increased both MAP and heart rate. The vasopressor response to footshocks was facilitated (p < 0.001) by i.p. administration of AFMH, a histidine decarboxylase inhibitor, or THIO, a H3-receptor antagonist, but not by i.v.t. injection of these drugs. AMH, a H3-receptor agonist, given i.p., decreased the vasopressor response to footshocks (p < 0.001). This action of AMH was abolished by THIO but not by mepyramine or cimetidine. The MAP response to exogenous norepinephrine was not altered by i.p. administration of either AFMH or THIO.. Our results demonstrate an involvement of peripheral histamine H3 prejunctional receptors in the inhibitory modulation of peripheral noradrenergic responses during stress.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cimetidine; Electric Stimulation; Enzyme Inhibitors; Heart Rate; Hindlimb; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Methylhistidines; Norepinephrine; Phentolamine; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Vasoconstrictor Agents

1. Rats were tested in an open field. Thioperamide given i.p. 30 minutes before the tests produced an increase of locomotor activity at 2 mg/kg and no behavioral effect at 5 mg/kg. 2. The repetition of the open field tests caused a reduction of ambulation in three successive tests. This effect was increased by thioperamide 2 and 5 mg/kg given after the tests, suggesting that this compound improved memory consolidation.

Topics: Animals; Dose-Response Relationship, Drug; Histamine Antagonists; Locomotion; Male; Memory; Piperidines; Rats; Rats, Wistar

Histamine elicits its biological effects via three distinct G protein-coupled receptors, termed H1, H2, and H3. We have used guanosine 5'-(gamma-[35S]thio)triphosphate (GTPgamma[35S]) autoradiography to localize histamine receptor-dependent G protein activation in rat brain tissue sections. Initial studies revealed that in basal conditions, adenosine was present in tissue sections in sufficient concentrations to generate an adenosine A1 receptor-dependent GTPgamma[35S] signal in several brain regions. All further incubations therefore contained 8-cyclopentyl-1,3-dipropylxanthine (10 microM), a selective A1 receptor antagonist. Histamine elicited dose-dependent increments in GTPgamma[35S] binding to discrete anatomical structures, most notably the caudate putamen, cerebral cortex, and substantia nigra. The overall anatomical pattern of the histamine-evoked binding response closely reflects the known distribution of H3 binding sites and was faithfully mimicked by N(alpha)-methylhistamine, (R)-alpha-methylhistamine, and immepip, three H3-selective agonists. In all regions examined, the GTPgamma[35S] signal was reversed with thioperamide and clobenpropit, two potent H3-selective antagonists, whereas mepyramine, a specific H1 antagonist, and cimetidine, a prototypic H2 antagonist, proved ineffective. These data indicate that in rat brain tissue sections, GTPgamma[35S] autoradiography selectively detects H3 receptor-dependent signaling in response to histamine stimulation. As the existing evidence suggests that GTPgamma[35S] autoradiography preferentially reveals responses to G(i/o)-coupled receptors, our data indicate that most, if not all, central H3 binding sites represent functional receptors coupling to G(i/o), the inhibitory class of G proteins. Besides allowing more detailed studies on H3 receptor signaling within anatomically restricted regions of the CNS, GTPgamma[35S] autoradiography offers a novel approach for functional in vitro screening of H3 ligands.

Topics: Adenosine; Animals; Autoradiography; Basal Ganglia; Brain Chemistry; Cerebral Cortex; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Male; Piperidines; Protein Binding; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3; Signal Transduction; Substantia Nigra; Sulfur Radioisotopes; Xanthines

We investigated the effects of histamine H3-receptor ligands on hippocampal synaptic transmission by using anesthetized rats in vivo. The medial perforant path was stimulated, and the population excitatory postsynaptic potential (pEPSP) and population spike were recorded from the granule cell layer of the dentate gyrus. Intracerebroventricular injection of the H3-receptor agonist (R)-alpha-methylhistamine decreased both the pEPSP and population spike, while H3-receptor antagonists, clobenpropit and thioperamide, increased both the pEPSP and population spike. These results suggest that the histaminergic system plays a role in inhibition of hippocampal synaptic excitation via the H3 receptor.

Topics: Animals; Dentate Gyrus; Excitatory Postsynaptic Potentials; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Male; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Synaptic Transmission; Thiourea

The effects of histamine H3-receptor antagonists, thioperamide, and clobenpropit on amygdaloid kindled seizures were investigated in rats. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injections of H3-antagonists resulted in a dose-related inhibition of amygdaloid kindled seizures. An inhibition induced by thioperamide was antagonized by an H3-agonist [(R)-alpha-methylhistamine] and H1-antagonists (diphenhydramine and chlorpheniramine). On the other hand, an H2-antagonist (cimetidine and ranitidine) caused no antagonistic effect. Metoprine, an inhibitor of N-methyltransferase was also effective in inhibiting amygdaloid kindled seizure, and this effect was augmented by thioperamide treatment.

Topics: Amygdala; Animals; Brain Chemistry; Enzyme Inhibitors; Histamine Antagonists; Histamine N-Methyltransferase; Imidazoles; Injections, Intraventricular; Kindling, Neurologic; Male; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

The concept of functional interaction between mast cells and intestinal afferents is gaining support. We have therefore characterized the action of histamine on jejunal afferent discharge in the anesthetized rat. Whole nerve mesenteric afferent discharge was recorded in conjunction with intestinal pressure in response to a range of histamine agonists and antagonists. Histamine at 2, 4, and 8 micromol/kg (iv) evoked a dose-dependent biphasic increase in afferent discharge together with a biphasic rise in intestinal pressure. However, these two events were mediated independently, since nifedipine (1 mg/kg) substantially reduced the intestinal pressure increase but not the afferent discharge. These responses were completely inhibited by pyrilamine (5 mg/kg) but unaffected by ranitidine (5 mg/kg) or thioperamide (2 mg/kg). Neither the selective H2 receptor agonist dimaprit nor the selective H3 receptor agonist R-alpha-methylhistamine caused any modulation of afferent discharge. We conclude that histamine stimulates an H1 receptor-mediated increase in mesenteric afferent discharge that is independent of intestinal motor events. This suggests that histamine potentially acts as a mediator in mast cell-to-afferent nerve communication in the small intestine.

Topics: Afferent Pathways; Animals; Blood Pressure; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Jejunum; Muscle, Smooth; Nifedipine; Piperidines; Pyrilamine; Ranitidine; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Splanchnic Circulation

The effects of histamine on high-voltage-activated Ca2+ channels in the histaminergic neurons acutely dissociated from the rat tuberomammillary nucleus were investigated in the nystatin-perforated patch recording mode under voltage-clamp conditions. Histamine suppressed the high-voltage-activated Ca2+ channel currents in neurons which were positive for histidine decarboxylase with immunocytochemistry. The half-maximum inhibitory concentration and maximum inhibition were 2.6 x 10(-7) M and 16.6+/-1.90%, respectively. An H3 receptor agonist, R(-)-alpha-methylhistamine, mimicked the response to histamine, and thioperamide, an H3 receptor antagonist, inhibited the response to histamine. On the other hand, neither 2-methylhistamine, an H1 receptor agonist, nor dimaprit, an H2 receptor agonist, had a significant effect on the Ca2+ channel currents. Pretreatment with pertussis toxin blocked the inhibitory effect of histamine on Ca2+ channels, suggesting the involvement of Gi/Go proteins in the action of histamine. Omega-conotoxin-GVIA, omega-agatoxin-IVA, nicardipine, and omega-conotoxin-MVIIC blocked the high-voltage-activated Ca2+ channel currents by 15.6, 4.3, 27.1, and 31.2% of the total current, respectively, suggesting the existence of N-, P-, L-, and Q-type Ca2+ channels. A current that was insensitive to these blockers was also found. This residual current, "R-type", was completely suppressed by the addition of 200 microM Cd2+. Histamine significantly inhibited both the N- and P-type current components among these five types of Ca2+ channel currents. We concluded that histamine suppresses the N- and P-type Ca2+ channels in histaminergic neurons through an H3 receptor which is linked to a pertussis toxin-sensitive G-protein.

Topics: Animals; Calcium; Calcium Channels; Calcium Channels, N-Type; Depression, Chemical; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Ion Channel Gating; Mammillary Bodies; Methylhistamines; Nerve Tissue Proteins; Neurons; Nicardipine; omega-Agatoxin IVA; omega-Conotoxin GVIA; omega-Conotoxins; Patch-Clamp Techniques; Peptides; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Spider Venoms; Tuber Cinereum; Virulence Factors, Bordetella

Whether or not neuropeptide Y (NPY)-induced feeding in rats is influenced by the histaminergic system in the brain was investigated by intracerebroventricular (i.c.v.) administration of a selective histamine H3 receptor antagonist prior to i.c.v. administration of NPY. NPY (10 microg/10 microl) strongly induced feeding in sated rats during the light phase of the day. Dynorphin A1-17 (10 microg/10 microl), a kappa-opioid agonist, and rat pancreatic polypeptide (rPP, 30 microg/10 microl) also stimulated ingestive behavior in sated rats, but food intake in both cases was less than that induced by NPY. Thioperamide maleate, a specific histamine H3 receptor antagonist (408.5 microg/10 microl) reduced the feeding response to NPY by 52% (P < 0.0001), but not to dynorphin A1-17 and rPP. Thioperamide at i.c.v. doses of 40.8-408.5 microg/10 microl had no effect on food intake in sated rats. These results suggest that the thioperamide may have a specific effect on NPY receptor-mediated neuronal systems related to feeding.

Topics: Animals; Dynorphins; Eating; Histamine Antagonists; Injections, Intraventricular; Male; Neuropeptide Y; Pancreatic Polypeptide; Peptide YY; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Receptors, Opioid, kappa

The long-term effects of portacaval anastomosis (PCA) on histamine H3 receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [3H]-R-alpha-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [3H]-R-alpha-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K+-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [3HI-R-alpha-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [3H]-R-alpha-methylhistamine binding density, particularly in striatum and cortex, where H3 receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H3 receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H3 receptors located at histaminergic neurons is preserved after long-term PCA.

Topics: Animals; Autoradiography; Body Weight; Brain; Cerebral Cortex; Histamine Antagonists; Histamine Release; Hypothalamus; Liver; Male; Microdialysis; Piperidines; Portacaval Shunt, Surgical; Radioligand Assay; Rats; Rats, Wistar; Receptors, Histamine H3; Weight Loss

The ability of histamine H3 receptor ligands to interact with 5-HT3 receptors in NG108-15 cells was studied using the whole cell patch clamp recording technique. Imetit, a histamine H3 receptor agonist, generated inward currents and exhibited weak partial agonist activity at the 5-HT3 receptor (EC50 = 11.8 microM). Imetit-induced currents were slow to desensitize and at a high concentration reduced in size. The histamine H3 receptor antagonists iodophenpropit and thioperamide did not generate inward currents but were able to inhibit 5-hydroxytryptamine (5-HT) responses with an IC50 of 1.57+/-0.3 microM and 13.7+/-3.5 microM, respectively. Thioperamide is probably a non-competitive antagonist which may have more than one binding site on the receptor.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Histamine Agonists; Histamine Antagonists; Hybrid Cells; Imidazoles; Ion Channels; Isothiuronium; Membrane Potentials; Mice; Piperidines; Rats; Receptors, Histamine H3; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Thiourea

Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.

Topics: Animals; Brain; Cell Membrane; Drug Design; Guinea Pigs; Histamine; Histamine Antagonists; Kinetics; Molecular Structure; Piperidines; Receptors, Histamine H3; Structure-Activity Relationship; Sulfonamides

We investigated the effect of the new potent and selective histamine H3 receptor agonist, immepip, and the histamine H3 receptor antagonist, clobenpropit, on in vivo neuronal histamine release from the anterior hypothalamic area of urethane-anesthetized rats, using microdialysis. Intrahypothalamic perfusion with immepip at concentrations of 1 and 10 nM reduced histamine release to 75% and 35% of its basal level, respectively. Peripheral injection of immepip (5 mg/kg) caused a sustained decrease in histamine release of 50%. Clobenpropit potently increased histamine release after intrahypothalamic perfusion. The maximal increase in histamine release was 2-fold, observed at a concentration of 10 nM clobenpropit. Peripheral injection of clobenpropit (5-15 mg/kg) increased histamine release to about 150% of the basal value. A more marked increase in histamine release was found after injection of the histamine H3 receptor antagonist, thioperamide (5 mg/kg). In conclusion, intrahypothalamic perfusion of the histamine H3 receptor agonist, immepip and the histamine H3 receptor antagonist, clobenpropit, potently and oppositely modulated in vivo histamine release from the anterior hypothalamic area. The decreased histamine release after peripheral injection of immepip indicates that this novel agonist readily crosses the blood-brain barrier, making it a potential candidate for in vivo histamine H3 receptor studies. The differential increase in histamine release after peripheral injection of clobenpropit and thioperamide is discussed.

Topics: Animals; Histamine Agonists; Histamine Antagonists; Histamine Release; Hypothalamus; Imidazoles; Injections, Subcutaneous; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea

We compared the effects of modulating the postsynaptic histamine receptor subtype 2 (H2) and inhibitory presynaptic autoreceptor subtype 3 (H3) on memory processing in the septum. Mice were partially trained on footshock avoidance in a T-maze. Immediately after training, saline or a drug solution was infused into the septum. One week later, retention was tested by continuing training until the mice made five avoidance responses in six consecutive trials. The results indicate that dimaprit, an H2 agonist, facilitated retention (25 and 50 pg) with a U-shaped dose-response curve typical of drugs acting at postsynaptic receptors. Cimetidine, an H2 antagonist, impaired retention (15-50 ng). The H3 agonist. imetit, impaired retention (25-200 ng), while the H3 antagonist, thioperamide, facilitated retention (10-400 ng). An unusual feature of the dose-response curve for thioperamide was that it did not appeal to yield a U-shaped curve as occurs with drugs acting postsynaptically, but facilitated retention to approximately the same degree from 50 to 400 ng. As histamine neurons project to various limbic system structures involved in memory processing, it may play an important role in regulating the activity of structures such as the septum, hippocampus and amygdala.

Topics: Animals; Cimetidine; Dimaprit; Histamine Agonists; Histamine Antagonists; Imidazoles; Limbic System; Male; Memory; Mice; Piperidines; Thiourea

In order to assess the role of histamine H3 receptors in the discriminative-stimulus effects of methamphetamine, rats were trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food presentation. The histamine H3 receptor antagonist thioperamide (1.0 mg/kg s.c.), which facilitates histamine release, significantly shifted the methamphetamine dose-response curve to the left when tested together with different doses of methamphetamine and markedly extended the time-course of methamphetamine's discriminative-stimulus effects. The histamine H3 receptor agonist R-alpha-methylhistamine (3.0 mg/kg i.p.), which blocks histamine release, did not produce any effects when given alone, but it attenuated the effects of thioperamide on the methamphetamine dose-response curve when both drugs were given together. Thus, methamphetamine's discriminative-stimulus effects are markedly potentiated by the blockade of histamine H3 receptors by thioperamide. This is likely due to thioperamide's actions at histamine H3 autoreceptors on histaminergic neurons to facilitate release of histamine by methamphetamine or at histamine H3 heteroreceptors on other monoaminergic neurons (e.g., dopaminergic, serotonergic or noradrenergic) to facilitate release of other neurotransmitters.

Topics: Animals; Central Nervous System Stimulants; Discrimination Learning; Dose-Response Relationship, Drug; Drug Synergism; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methamphetamine; Methylhistamines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Time Factors

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

The effects of intra-arterial injection of different doses of the selective histamine H3-receptor agonist R-alpha-methylhistamine and the selective histamine H3-receptor antagonist thioperamide on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure (MAP) and heart rate (HR) were investigated in permanently instrumented freely moving rats. R-alpha-Methylhistamine (0.01, 0.1 and 1 mumol/kg) inhibited the evoked noradrenaline overflow up to 43%, the ED50 value being 0.013 mumol/kg. Thioperamide (0.1, 0.5 and 1.0 mumol/kg) antagonized the effect of 1.0 mumol/kg R-alpha-methylhistamine dose-dependently, evoked overflow returning to control values at 1.0 mumol/kg of the antagonist; thioperamide alone had no effect on electrically evoked noradrenaline overflow. Basal noradrenaline levels, blood pressure and heart rate were not at all influenced by R-alpha-methylhistamine and thioperamide, alone or in combination. The results clearly show the presence of prejunctional histamine H3-receptors inhibiting the electrically evoked noradrenaline overflow from vascular sympathetic nerve terminals in the portal vein of freely moving rats.

Topics: Animals; Blood Pressure; Electric Stimulation; Heart Rate; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Norepinephrine; Piperidines; Portal Vein; Rats; Rats, Wistar; Receptors, Histamine H3

Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H3 receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which new H3 receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H3 receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension. All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 mumol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H3 receptor agonists, R-(-)-alpha-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H3 binding sites (labelled by 3H-N alpha-methylhistamine; pKi 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 mumol/kg to about the same degree in rats of either strain. The present study confirms the occurrence of presynaptic H3 receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H3 receptors are

Topics: Adrenergic Fibers; Animals; Blood Pressure; Decerebrate State; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Hypertension; Imidazoles; Male; Methylhistamines; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagotomy; Vascular Resistance

A recent study showed that SKF92374, a structural analog of the histamine H2 receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked significant activity on H1 or H2 receptors, but had weak activity on H3 receptors. To test the hypothesis that SKF92374-induced antinociception is mediated by an action on H3 receptors, the effects of the H3 agonist R-alpha-methylhistamine (RAMH) and the H3 antagonist thioperamide (both by i.v.t. administration) were investigated on SKF92374 antinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 microg), but unaffected by a range of doses of RAMH (up to 2 microg). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H1 (pyrilamine), H2 (zolantidine), H3 (GT-2016), or opioid (naltrexone) receptors. These findings show that the novel compound SKF92374 induces antinociception by a non-opioid mechanism that does not utilize brain H1, H2 or H3 receptors.

Topics: Analgesics, Non-Narcotic; Animals; Cimetidine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Naltrexone; Narcotic Antagonists; Nociceptors; Piperidines; Rats; Rats, Sprague-Dawley; Stereoisomerism

In this study, we have characterized the phenotype of mast cells in rat dura mater and their topological and functional relationships with C-fibers in normal and inflammatory conditions. Three mast cell populations with different size, morphology and localization were characterized by their content of specific neutral serine proteases. They showed immunoreactivity corresponding to rat mast cell protease I, rat mast cell protease II, or both proteases. Using confocal microscopy, all three mast cell types were observed in close apposition (distance less than 100 nm) to calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in both controls and rats infected with the nematode Nippostrongylus brasiliensis. After nematode infection or neonatal treatment with capsaicin, a large increase in the number of rat mast cell protease II-immunoreactive mast cells was found within dura mater segments (+1478% and +596%, respectively), without concomitant changes of rat mast cell protease I- or rat mast cell protease I/II-immunoreactive mast cells. Under both these conditions, the increase in mast cell number was accompanied by a significant increase in rat mast cell protease II level within tissue extracts (+281% after nematode infection and +36% after capsaicin treatment). The functional interaction of mast cells with sensory nerve fibers in the dura mater was assessed by evaluating [3H]histamine synthesis after administration of L-[3H]histidine, an index of mast cell activity. The H3 receptor agonist (R)-alpha-methylhistamine (15 mg/kg, i.p.) had no effect, but administration of the H3 receptor antagonist, thioperamide (10 mg/kg, i.p.), resulted in a significant increase of [3H]histamine synthesis (+62%). This effect was reduced in neonatal capsaicin-treated rats, but not completely suppressed (+35%), very likely because of partial denervation, as assessed by monitoring calcitonin gene-related peptide immunoreactivity. It is concluded that, in the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.

Topics: Animals; Animals, Newborn; Capsaicin; Cerebral Cortex; Chymases; Denervation; Dura Mater; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine Antagonists; Inflammation; Male; Mast Cells; Methylhistamines; Nerve Fibers; Neurons, Afferent; Nippostrongylus; Piperidines; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Strongylida Infections

Topics: Animals; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Imidazoles; Intestine, Small; Male; Methylhistamines; Muscle Contraction; Peristalsis; Piperidines; Receptors, Histamine H3; Thiourea

In order to obtain a new, potent and selective histamine H3 receptor antagonists, chemical modifications of thioperamide, a well-known H3 receptor antagonist, were conducted. A new series of compounds has been synthesized by modifying the thiourea and cyclohexyl groups of thioperamide, and tested for H3 affinity by receptor binding assay using plasma membrane from rat cerebral cortex. The thiourea group of thioperamide was found to be replaceable with a basic moiety such as formamidine or S-methylisothiourea. Replacement of the cyclohexyl group in thioperamide by a 1-adamantyl or an exo-2-norbornyl group increased the affinity for H3 receptor. Among the compounds synthesized, N-(1-adamantyl)-N',N'-[3-(4(5)-1H-imidazolyl)pentamethylene] formamidine 3f (AQ0145) showed the highest H3 receptor affinity, having a potent antagonistic activity. This compound was at least 1,000-fold more active towards H3 than towards H1 and H2 receptors.

Topics: Amidines; Animals; Cerebral Cortex; Guinea Pigs; Histamine Antagonists; Isothiuronium; Piperidines; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

Using an in vivo microdialysis method, we measured the release of histamine in the anterior hypothalamic area (AHy) of rats under several concentrations of halothane anesthesia (1, 0.5, and 0.2%). The release of histamine increased to 341 and 325% at halothane concentrations of 0.5 and 0.2%, compared with the basal level at anesthesia induced by 1% halothane. alpha-Fluoromethylhistidine (100 mg/kg i.v.), a specific and irreversible inhibitor of histidine decarboxylase, reduced the histamine release to <35% of the basal value at 1% halothane anesthesia in the AHy, and also decreased the anesthetic requirement for halothane, evaluated as the minimum alveolar concentration (MAC), by 26%. Furthermore, pyrilamine (20 mg/kg i.v.), a brain-penetrating H1 antagonist, and zolantidine (20 mg/kg i.v.), a brain-penetrating H2 antagonist, reduced the MAC for halothane by 28.5 and 16%, respectively. Although thioperamide (5 mg/kg i.v.), an antagonist of presynaptic H3 autoreceptor, induced an approximate twofold increase in the level of histamine release in conscious freely moving rats, the same dose of thioperamide had little effect on the release of histamine under 1% halothane anesthesia in the AHy. Furthermore, thioperamide did not change the anesthetic requirement (MAC) for halothane. The present findings indicate that halothane anesthesia inhibits the release of neuronal histamine and that histaminergic neuron activities change the anesthetic requirement (MAC) for halothane through H1 as well as H2 receptors.

Topics: Anesthetics, Inhalation; Animals; Benzothiazoles; Drug Interactions; Enzyme Inhibitors; Halothane; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine Release; Male; Methylhistidines; Microdialysis; Neurons; Phenoxypropanolamines; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Thiazoles

Histamine is likely involved in vestibular function recovery since histaminergic medications are effective in vestibular-related syndromes. We investigated the histamine immunoreactivity changes after unilateral vestibular neurectomy and the effects of betahistine (a partial histamine H1 receptor agonist and an histamine H3 receptor antagonist) and thioperamide (a pure histamine H3 receptor antagonist) treatment in cats. Histamine staining was analyzed in the tuberomammillary and vestibular nuclei through immunohistochemical methods and quantification techniques in light microscopy. Unilateral vestibular neurectomy induced a strong bilateral decrease in histamine immunoreactivity in the vestibular nuclei and a smaller reduction in the tuberomammillary nuclei in both acute (1 week) and compensated (3 weeks, 1 year) cats. One-week thioperamide or betahistine treatment led to a near-total lack of staining in these structures in both lesioned and control cats. One-month betahistine treatment had weaker effects in the compensated cats. We conclude that vestibular lesions reduce histamine staining because of an increase in histamine release in the vestibular and tuberomammillary nuclei, promoting vestibular functions recovery, and betahistine could contribute to this process by acting on both the presynaptic histamine H3 and postsynaptic histamine H1 receptors.

Topics: Animals; Betahistine; Cats; Histamine; Histamine Agonists; Hypothalamus; Immunohistochemistry; Piperidines; Vestibular Nerve; Vestibular Nuclei

We examined the possible existence of prejunctional histamine H3 receptors on sympathetic nerve fibers innervating rat tail artery. The stimulation-evoked tritium outflow from isolated vessels preincubated with [3H]-noradrenaline and perfused/superfused in the presence of the alpha2-adrenoceptor antagonist rauwolscine, 3 microM, was inhibited by histamine 10 microM (by 8%) and the H3 agonists R-(-)-alpha-methylhistamine, 10 microM (by 18%), and imetit, 0.1-10 microM (by < or =20%). The inhibitory effect of imetit, which did not occur in the absence of rauwolscine, was counteracted by thioperamide, 1 microM. In the presence of rauwolscine, 3 microM, the inhibitory effect of imetit also occurred when the current strength or the Ca2+ concentration in the medium was reduced to compensate for the increase in tritium overflow elicited by rauwolscine, indicating that the inhibitory action of imetit is not associated with the increase in noradrenaline release produced by rauwolscine. In spontaneously hypertensive rats (SHRs), imetit also inhibited the overflow of tritium. This inhibitory effect was comparable to that observed in Wistar-Kyoto (WKY) rats and indicates that the sympathetic nerves of the rat tail artery in SHRs, like those in normotensive rats, are endowed with prejunctional histamine H3 receptors.

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Arteries; Electric Stimulation; Histamine; Histamine Agonists; Imidazoles; Male; Norepinephrine; Piperidines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Histamine H3; Sympathetic Fibers, Postganglionic; Thiourea; Yohimbine

The present study was designed to examine the functional linkage between histamine and somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Superfusion with somatostatin antibody (1:250) increased histamine secretion, implying that endogenous somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. We conclude that fundic histamine and somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Topics: Animals; Antibodies; Gastric Fundus; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; Kinetics; Methacholine Chloride; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3; Somatostatin; Virulence Factors, Bordetella

The present study examined the effects of histamine in the guinea pig isolated vestibular hair cells (VHCs) by measuring the dynamic changes of intracellular free calcium ion ([Ca2+]i) concentration using calcium sensitive dye Fura-2. The histamine-induced calcium response in VHCs was markedly increased at the concentration of 10 microM histamine in the presence of extracellular Ca2+, while in the absence of extracellular Ca2+, a slow increase of [Ca2+]i was evident. Receptor specificity of the response to histamine was examined: promethazine (H1 receptor antagonist), cimetidine (H2 receptor antagonist) and thioperamide (H3 receptor antagonist) completely blocked the histamine-induced calcium response at the concentrations of 2.5 microM, 1.0 microM and 1.0 nM, respectively. The responses were mediated by H1, H2 and H3 receptors and resulted in a rise of [Ca2+]i due to an influx of Ca2+ from the extracellular space and a release from intracellular stores. Our preliminary data suggest that under immuno-pathological conditions of the inner ear, histamine released from the mast cells distributed in the endolymphatic sac may act through receptors located on the vestibular hair cell membrane and may regulate the cell function and the signal transduction in the vestibular nerve-hair cell afferent system.

Topics: Afferent Pathways; Animals; Calcium; Cimetidine; Cytoplasm; Endolymphatic Sac; Extracellular Space; Fluorescent Dyes; Fura-2; Guinea Pigs; Hair Cells, Vestibular; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine Release; Mast Cells; Piperidines; Promethazine; Receptors, Cell Surface; Signal Transduction; Vestibular Nerve

The effects of adenosine and histamine 2 and histamine 3 receptor agonists on the regulation of gastric histamine release were examined in anesthetized mixed-breed dogs. All compounds were infused directly into the gastrosplenic artery to avoid perturbations in systemic hemodynamics, and the gastric histamine release was stimulated with pentagastrin. The histamine concentration in plasma samples was measured utilizing gas chromatography-negative-ion chemical ionization mass spectroscopy. Pentagastrin consistently stimulated gastric histamine release with the peak stimulation occurring at 5 min, while neither 30 nor 100 microM of adenosine altered the effect of pentagastrin on histamine release. In addition, theophylline at 20 microg/ml exhibited no effect on stimulated histamine release. The histamine 2 receptor agonist dimaprit, at 1 and 3 microM, attenuated pentagastrin-stimulated histamine release at the 5-min time period, but the difference was not sustained at later time points (histamine release from 1.4 +/- 0.6 to 92 +/- 18 ng/min at 5 min with pentagastrin alone; from 1.2 +/- 0.5 to 32 +/- 11 ng/min with pentagastrin plus 1 microM dimaprit, and from 2.0 +/- 1.1 to 32 +/- 9 ng/min with pentagastrin plus 3 microM dimaprit), while the H2 receptor antagonist cimetidine exhibited no effect on pentagastrin-stimulated histamine release. The histamine 3 receptor agonist (R)-alpha-methylhistamine attenuated the pentagastrin-stimulated histamine release at the 5- and 10-min time periods only at 1 microM without showing any effect at the higher (3 microM) concentration. Thioperamide, a H3 receptor antagonist, did not modify pentagastrin-stimulated histamine release. These data demonstrate that adenosine has no modulatory role on gastric histamine release, but histamine via H2 and H3 histamine receptors could modulate its own release but only to a modest degree as compared with the potent effect of the paracrine hormone somatostatin.

Topics: Adenosine; Animals; Dimaprit; Disease Models, Animal; Dogs; Female; Gas Chromatography-Mass Spectrometry; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Multivariate Analysis; Pentagastrin; Piperidines; Receptors, Histamine; Reference Values; Regional Blood Flow; Statistics, Nonparametric; Theophylline

Using a microdialysis method and a new high performance liquid chromatography (HPLC)-fluorometric method for the detection of gamma-aminobutyric acid (GABA), we investigated the effect of thioperamide, an H3 receptor antagonist, on the GABA content in the dialysate from the anterior hypothalamic area of rats anesthetized with urethane. The addition of thioperamide to the perfusion fluid increased the release of GABA and histamine. Depleting neuronal histamine with alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, and the administration of immepip, an H3 agonist, had no effect on basal- and thioperamide-induced GABA release. In addition, an infusion of clobenpropit, the most specific H3 receptor antagonist available, did not alter the basal release of GABA. On the other hand, histamine release was decreased by immepip and increased by thioperamide and clobenpropit. Removing Ca2+ from the perfusion fluid did not alter the effect of thioperamide on the GABA release, whereas that on histamine release was abrogated. These results suggest that the effect of thioperamide on GABA release is not mediated by histamine H3 receptors and that thioperamide acts on the transporter to cause an efflux of GABA from neurons and/or glia. Thioperamide is a popular H3 receptor antagonist which has been used applied to many studies. However, results using this compound should be interpreted in consideration of its effects on GABA release.

Topics: Animals; Calcium; Enzyme Inhibitors; gamma-Aminobutyric Acid; Histamine Agonists; Histamine Antagonists; Histidine Decarboxylase; Hypothalamus; Imidazoles; Male; Methylhistidines; Microdialysis; Neurons; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea

Responses to T-kinin and bradykinin were compared in the mesenteric vascular bed of the cat. Under constant-flow conditions, injection of T-kinin and bradykinin into the perfusion circuit induced similar dose-related decreases in perfusion pressure. Responses to T-kinin and bradykinin were inhibited by the kinin B2 receptor antagonist Hoe-140, but were not altered by the B1 receptor antagonist des-Arg9-[Leu8]-BK, the histamine H1 antagonist pyrilamine, the histamine H2 receptor antagonist cimetidine, or the H3 receptor antagonist thioperamide. Vasodilator responses to T-kinin and bradykinin were attenuated by the nitric oxide synthase inhibitor, N omega Nitro-L-arginine methyl ester (L-NAME), but were not altered by the cyclooxygenase inhibitor, sodium meclofenamate, or the K+ ATP channel antagonist, U37883A. These data suggest that vasodilator responses to T-kinin and bradykinin are mediated by kinin B2 receptor stimulated release of nitric oxide from the endothelium, but that the activation of kinin B1 receptors, the release of vasodilator prostaglandins, or the opening of K+ ATP channels are not involved in the response to T-kinin in the mesenteric vascular bed of the cat.

Topics: Adamantane; Analysis of Variance; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cats; Cimetidine; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Female; Histamine Antagonists; Male; Meclofenamic Acid; Mesentery; Morpholines; NG-Nitroarginine Methyl Ester; Piperidines; Potassium Channels; Pyrilamine

Recent studies have shown that cimetidine, burimamide and improgan (also known as SKF92374, a cimetidine congener lacking H2 antagonist activity) induce antinociception after intracerebroventricular administration in rodents. Because these substances closely resemble the structure of histamine (a known mediator of some endogenous analgesic responses), yet no role for known histamine receptors has been found in the analgesic actions of these agents, the structure-activity relationships for the antinociceptive effects of 21 compounds chemically related to H2 and H3 antagonists were investigated in this study. Antinociceptive activity was assessed on the hot-plate and tail-flick tests after intracerebroventricular administration in rats. Eleven compounds induced time-dependent (10-min peak) and dose-dependent antinociceptive activity with no observable behavioral impairment. ED50 values, estimated by nonlinear regression, were highly correlated across nociceptive assays (r2 = 0.98, n = 11). Antinociceptive potencies varied more than 6-fold (80-464 nmol), but were not correlated with activity on H1, H2 or H3 receptors. Although highly potent H3 antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H3 antagonist activity and also showed potent, effective analgesia. A literature review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the present results suggest: 1) these compounds act on the brain to activate powerful analgesic responses that are independent of known histamine receptors, 2) the structure-activity profile of these agents is novel and 3) brain-penetrating derivatives of these compounds could be clinically useful analgesics.

Topics: Analgesics, Non-Narcotic; Animals; Burimamide; Dose-Response Relationship, Drug; Histamine Antagonists; Histamine H2 Antagonists; Imidazoles; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Structure-Activity Relationship; Thiourea

To determine whether histamine affects airway goblet cell secretion and, if so, whether cholinergic mechanism is involved, we studied guinea pig airways by a semiquantitative morphometric method. The goblet cell secretion was assessed in histologic sections of the tracheal mucosa stained with Alcian blue and periodic acid-Schiff (PAS) by determining the mucus score, which is inversely related to the magnitude of mucus discharge. Inhaled or intravenously administrated histamine dose dependently decreased the mucus score, an effect that was similarly observed in cartilaginous and muscular portions. Inhalation of the anticholinergic agent oxitropium bromide at doses of 1.5 micrograms and higher greatly attenuated the decrease in mucus score produced by intravenous histamine but not by inhaled histamine. Likewise, cutting of bilateral vagus nerves or atropine abolished intravenous histamine-induced goblet cell secretion. The response of the mucus score to inhaled histamine was abolished by cimetidine, whereas the response to intravenous histamine was reduced by mepyramine but not by cimetidine or thioperamide. These results suggest that inhaled histamine increases airway goblet secretion, probably by stimulating histamine H2-receptors on goblet cells, and that intravenous histamine produces a similar effect through a stimulation of histamine H1-receptor-mediated release of acetylcholine from cholinergic nerve terminals, presumably involving vagal reflex.

Topics: Administration, Inhalation; Aerosols; Animals; Atropine; Cimetidine; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Antagonists; Histocytochemistry; Injections, Intravenous; Male; Mucus; Muscarinic Antagonists; Piperidines; Pyrilamine; Receptors, Histamine; Scopolamine Derivatives; Trachea; Vagus Nerve

The histamine forming capacity (HFC) of acutely challenged airways from sensitised guinea pigs was investigated. After exposure to nebulised bovine serum albumin (BSA) or normal saline, animals were sacrificed, the pulmonary HFC determined and concurrent in vitro histamine log concentration response curves were constructed for parenchymal strips and tracheal muscle, the latter was field stimulated to record neurogenic responses. Exposure to BSA increased the HFC above controls for 24 hours (p < 0.001) and log concentration response curves for the parenchymal strips were shifted slightly to the left with an increased maximum response. This change appeared 3 hours after exposure and remained elevated at 24 hours. Similar changes did not occur with the trachea. Pre-treatment with thioperamide augmented (p < 0.02) HFC and this increase was inhibited by alpha-methylhistamine (p < 0.05). A possible relationship may exist between increased responsiveness of lower airways to exogenous histamine and a raised endogenous formation, regulated by the H3 receptor.

Topics: Animals; Binding Sites; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Ligands; Lung; Male; Methylhistamines; Muscle, Smooth; Piperidines; Receptors, Histamine H3; Serum Albumin, Bovine; Trachea

Topics: Acetylcholine; Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Microdialysis; Neurons; Parietal Lobe; Piperidines; Potassium; Rats; Rats, Wistar; Receptors, Histamine H3; Thiazoles

Topics: Analysis of Variance; Animals; Brain; Dopamine; Histamine; Histamine Agonists; Histamine Antagonists; Homovanillic Acid; Hydroxyindoleacetic Acid; Hypothalamus; Injections, Intraventricular; Male; Methylhistamines; Norepinephrine; Piperidines; Portacaval Shunt, Surgical; Prolactin; Rats; Rats, Wistar; Receptors, Histamine H3; Serotonin

We determined the affinities of 16 newly synthesized H3 receptor antagonists in an H3 receptor binding assay and the potencies of 12 of these compounds at functional H3 receptors in the mouse brain cortex and guinea-pig ileum. The compounds differ from histamine in that the C-C-N side chain is replaced by a chain of the structure C-C-C-O. The two major aims of the study were (1) to investigate whether the two functional H3 receptors are pharmacologically different and (2) to derive structure-activity relationships. The specific binding of 3H-Na-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the 16 compounds at pKi values ranging from 7.30 to 9.48. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically evoked tritium overflow was slightly decreased by iodoproxyfan and its deiodo analogue; this effect was counteracted by the H3 receptor antagonist clobenpropit. The other compounds did not affect the evoked tritium overflow by themselves. The concentration-response curve of histamine for its inhibitory effect on the electrically evoked tritium overflow was shifted to the right by the 12 compounds with apparent pA2 values ranging from 7.02 to 9.00. The 12 compounds also shifted to the right the concentration-response curve of R-a-methylhistamine for its inhibitory effect on the electrically induced contraction in guinea-pig ileum strips; the apparent pA2 values ranged from 5.97 to 9.00. Iodoproxyfan decreased the electrically induced contraction by itself and this effect was counteracted by the H3 receptor antagonist thioperamide. The apparent pA2 values in the two functional H3 receptor models showed a highly significant correlation (r = 0.882; P < 0.001). Highly significant correlations were also obtained when the pKi values of the compounds in the binding assay were compared to their apparent pA2 values in the mouse brain (r = 0.799; P < 0.004) and in the guinea-pig ileum (r = 0.851; P < 0.001). In each of the three experimental models, iodoproxyfan was the most potent compound; its deiodo analogue was less potent by more than 1.1 log units. The present results show that the compounds under study possess moderate to high affinity and/or (partial) H3 receptor antagonist potency. The two functional H3 receptors in the mouse brain cortex and the guinea-pig ileum may be slightly different; further studies are necessary to clarify whether this difference is due to H3 receptor heterogen

Topics: Animals; Binding, Competitive; Cerebral Cortex; Dose-Response Relationship, Drug; Female; Guinea Pigs; Histamine Antagonists; Histamine H2 Antagonists; Imidazoles; In Vitro Techniques; Intestine, Small; Iodine Radioisotopes; Male; Methylhistamines; Mice; Piperidines; Rats; Rats, Wistar; Structure-Activity Relationship

Murine hematopoietic progenitor cells synthesize substantial amounts of histamine in response to IL-3 or calcium ionophore. They also take up extracellular histamine by an active transport system. In the present study we demonstrate that this system mediates both influx and efflux of histamine. Indeed, MR16155 and thioperamide, the two H3 antagonists which are most effective in inhibiting histamine uptake, likewise diminish the release of preloaded histamine from bone marrow cells. These compounds also inhibit the release of histamine which has been newly synthesized by hematopoietic progenitors in response to IL-3 or calcium ionophore, as assessed by the accumulation of the mediator inside the cells in the presence of the antagonists. The potency of different histamine receptor antagonists as inhibitors of histamine release increases with their capacity to block histamine uptake.

Topics: Animals; Biological Transport; Calcium; Cell Line; Cetirizine; Cimetidine; Female; Hematopoietic Stem Cells; Histamine; Histamine Antagonists; Interleukin-3; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrimidinones; Sodium

Thioperamide (2 mg/kg, l.p.), a histamine H3-receptor antagonist, increased the number of somatostatin (SS) receptors, with no change in the affinity constant, in the rat frontoparietal cortex. This effect was prevented by treatment with (R)-alpha-methylhistamine (3.2 mg/kg, l.p.), a histamine H3-receptor agonist. Thioperamide also induced an increase in SS binding in rats pretreated with mepyramine, a histamine H1-receptor antagonist, or cimetidine, a histamine H2-receptor antagonist. Pretreatment with mepyramine plus cimetidine administered simultaneously antagonized the thioperamide effect on SS binding. The increase in the number of SS receptors was accompanied by a greater SS-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase (AC) activity in frontoparietal cortical membranes in the thioperamide group. Furthermore, the functional activity of the guanine nucleotide-binding inhibitory protein (G1 protein) was not altered by thioperamide or (R)-alpha-methylhistamine administration in frontoparietal cortical membranes. In rats treated with mepyramine plus thioperamide or cimetidine plus thioperamide, the increase in the number of SS receptors was also accompanied by an increased SS inhibition of AC activity. Thioperamide induced a significant increase in SS-like immunoreactivity content in the frontoparietal cortex. Altogether, these results suggest that frontoparietal cortical histamine may play, at least in part, a role in the regulation of the somatostatinergic system.

Topics: Adenylyl Cyclases; Animals; Colforsin; Frontal Lobe; GTP-Binding Proteins; Histamine Agonists; Histamine Antagonists; Methylhistamines; Parietal Lobe; Piperidines; Presynaptic Terminals; Rats; Rats, Wistar; Receptors, Histamine H3; Receptors, Somatostatin; Somatostatin

Effects of histamine and related compounds on the bovine iris dilator were investigated. Histamine caused a concentration-related contraction of the bovine iris dilator and IC50 was 1.57 x 10(-7) M. The potency of histamine on the bovine iris dilator was almost the same as that observed in guinea pig ileum. Histamine-induced contraction of the bovine iris dilator was antagonized by the H1 antagonists pyrilamine, diphenhydramine and chlorpheniramine, whereas pretreatment with the H2 antagonists cimetidine and ranitidine was most effective. In addition, histamine and the H1 agonist 2-methylhistamine caused a contraction of bovine iris dilator, but the H2 agonist 4-methylhistamine was not effective. An H3 antagonist, thioperamide, also had no contractive effects on the bovine iris dilator. The bovine iris dilator contained a considerable amount of histamine, which was not released by compound 48/80, substance P or by increasing K+ concentration in the medium. In conclusion, histamine caused a potent contraction of the bovine iris dilator via H1 receptor, and this muscle showed a high sensitivity to histamine similar to guinea pig ileum.

Topics: Analysis of Variance; Animals; Cattle; Chlorpheniramine; Cimetidine; Diphenhydramine; Dose-Response Relationship, Drug; Female; Guinea Pigs; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Ileum; Iris; Lethal Dose 50; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; p-Methoxy-N-methylphenethylamine; Piperidines; Potassium; Pyrilamine; Ranitidine; Receptors, Histamine H1; Substance P

The histamine H3 receptor has been shown to inhibit pentagastrin-induced gastric acid secretion in dogs. Since pentagastrin releases histamine in dogs, we have now assessed whether the effects of H3-receptor ligands may be indirectly mediated by changes in gastric histamine release.. Pentagastrin infusions (1 or 6 micrograms/kg/h), alone or together with the H3-receptor agonist (R) alpha-methylhistamine (1.2 mumol/kg/h) or the antagonist thioperamide (0.1 mumol/kg/h), were performed in dogs. One group (anaesthetized) was used for enzyme immunoassays of plasma histamine and, when required. (R) alpha-methylhistamine in the gastrosplenic vein, and another group (non-anaesthetized) for measurement of gastric acid secretion.. Histamine levels were increased five- and eight-fold after 1 and 6 micrograms/kg/h pentagastrin, respectively, whereas acid output was nearly maximal at the lower dosage. (R) alpha-methylhistamine, at a plasma concentration of 0.15 microM, inhibited histamine release by 78% (P < 0.007) and 37% (not significant) and the total acid output by 44% (P < 0.05) and 19% (not significant) after infusion of 1 and 6 micrograms/kg/h pentagastrin, respectively. Thioperamide, together with pentagastrin in low dose, significantly increased histamine release by 212% (P < 0.05), whereas acid output increased by 34% (not significant).. The histamine H3 receptor mediates a negative feedback control of pentagastrin-induced release of gastric histamine. It is tonically activated by endogenous histamine after pentagastrin in low dosage. The control of acid secretion by the H3 receptor seems to involve modulation of endogenous histamine release, possibly by means of enterochromaffin-like cells.

Topics: Animals; Dogs; Female; Gastric Acid; Gastric Mucosa; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Pentagastrin; Piperidines; Receptors, Histamine H3

We examined whether a histamine (H3)-agonist, (R) alpha-methylhistamine, [(R) alpha-MeHA] reduced the pressor responses induced by nicotine in urethane-anesthetized guinea pigs treated by atropine. Nicotine dose-dependently increased the basal mean arterial pressure (MAP) and the heart rate (HR) of the preparation. Both effects were due to stimulation of sympathetic ganglia, since muscarinic receptors were blocked. Adrenalectomy did not affect either the hypertension or the tachycardia to nicotine. Nicotine (7 micrograms kg-1) evoked a transient hypertension of approximately 30 mm Hg and a tachycardia by approximately 20 beats/min. (R) alpha-MeHA dose-dependently inhibited the increase in mean arterial pressure and the increase in HR to nicotine but not those produced by exogenous norepinephrine (NE). The inhibitory effects of (R) alpha-MeHA were dose-dependently antagonized by the H3-antagonist thioperamide, but not by combined mepyramine/cimetidine. They were also suppressed by a nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME); this suppression was reversed by L-arginine. Histamine in the presence of mepyramine and cimetidine induced a similar inhibition of the hypertension to nicotine but a less potent inhibition of the tachycardia. These findings indicate that postganglionic noradrenergic nerve fibers are endowed with presynaptic H3-receptors, the stimulation of which inhibits NE release through an NO mechanism.

Topics: Adrenalectomy; Animals; Arginine; Blood Pressure; Cimetidine; Guinea Pigs; Heart Rate; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; NG-Nitroarginine Methyl Ester; Nicotine; Nitric Oxide Synthase; Piperidines

Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and CD49d molecules on eosinophils is thought to mediate the selective infiltration of eosinophils into inflamed tissues in allergic disease. IL-4 and TNF-alpha are associated with allergic conditions, and they have been shown to selectively augment VCAM-1 expression on endothelial cells, suggesting that they may be responsible for VCAM-1 expression in allergic disease. We used immunocytochemical staining analysis to examine the effect of chemical mediators, including histamine, leukotrienes and platelet-activating factor (PAF), on VCAM-1 expression in IL-4- and TNF-alpha-stimulated endothelial cells. Histamine, significantly augmented (p < 0.05 to p < 0.01) VCAM-1 expression in both IL-4- and TNF-alpha-stimulated endothelial cells. IL-4 and TNF-alpha were found to have a synergistic effect on endothelial cell VCAM-1 expression, when compared with the effect of stimulation with each of these cytokines separately, and the addition of histamine further increased VCAM-1 expression. This enhancing effect of histamine was inhibited by the presence of mepyramine and thioperamide but not by cimetidine. Another chemical mediator, PAF, failed to induce any increase in VCAM-1 expression, however, leukotrienes augmented it slightly in a narrow range of concentrations. The histamine-induced augmentation of VCAM-1 expression was reflected functionally by many more eosinophils attaching to endothelial cells than to cells stimulated with both cytokines. This attachment of eosinophils was inhibited by the presence of antibody to VCAM-1 and CD49d. Addition of histamine 10 h after stimulation with both cytokines still induced an increase in VCAM-1 expression. In addition, an inhibitor of RNA polymerase, alpha-amanitin, dose-dependently decreased this histamine-induced augmentation of VCAM-1 expression. These findings strongly suggest that histamine upregulates VCAM-1 expression at the transcriptional level through newly generated of mRNA in endothelial cells stimulated with IL-4 and TNF-alpha.

Topics: Amanitins; Antibodies, Blocking; Antigens, CD; Cell Adhesion; Cells, Cultured; Cimetidine; Eosinophils; Histamine; Histamine Antagonists; Humans; Immunohistochemistry; Integrin alpha4; Interleukin-4; Piperidines; Platelet Activating Factor; Pyrilamine; Tumor Necrosis Factor-alpha; Umbilical Veins; Vascular Cell Adhesion Molecule-1

1. The purpose of the present study was to characterize the binding of the histamine H3 receptor antagonist, [3H]-thioperamide, to rat cerebral cortical membranes. 2. The binding of [3H]-thioperamide to rat cerebral cortical membranes reached equilibrium after incubation with [3H]-thioperamide after 8-10 h at 4 degrees C. Equilibrium was maintained for up to 18 h of incubation. Addition of 1 microM (R)-alpha-methylhistamine rapidly dissociated [3H]-thioperamide from its binding sites. From these kinetic experiments a dissociation constant of 0.3 nM was obtained for [3H]-thioperamide. 3. Saturation experiments with [3H]-thioperamide using 1 microM (R)-alpha-methylhistamine to define nonspecific binding were best analysed according to a single site model. A dissociation constant (KD) of 0.80 +/- 0.06 nM (n = 3) and a maximal number of binding sites (Bmax) of 73 +/- 20 fmol mg-1 protein (n = 3) were obtained for the binding of [3H]-thioperamide to rat cerebral cortical membranes. 4. Saturation experiments with [3H]-thioperamide using 0.3 microM iodophenpropit to define nonspecific binding were best analysed according to a two site model. For the high affinity [3H]-thioperamide site a KD value of 1.1 +/- 0.3 nM (n = 3) and Bmax value of 162 +/- 108 fmol mg-1 protein (n = 3) were obtained whereas KD and Bmax values for the low affinity site were 96 +/- 19 nM and 4346 +/- 3092 fmol mg-1 protein (n = 3), respectively. 5. Using 5 nM [3H]-thioperamide, the binding was hardly displaced by H3 agonists within concentration-ranges expected to bind to the histamine H3 receptor. Under these conditions, [3H]-thioperamide binding was fully displaced by various H3-antagonists, yet most H3 antagonists showed Ki values different from those expected for the histamine H3 receptor. 6. Using 0.3 nM [3H]-thioperamide, 50-60% of the total binding was potently displaced by the H3 agonists histamine, (R)-alpha-methylhistamine, (S)-alpha-methylhistamine, imetit and immepip. Displacement of the binding of 0.3 nM [3H]-thioperamide binding exhibited clear stereoselectivity for the R and S isomers of alpha-methylhistamine. 7. Binding of 0.3 nM [3H]-thioperamide was completely displaced by several H3 antagonists (thioperamide, iodophenpropit, iodoproxyfan, and burimamide) and biphasic displacement curves were obtained; the Ki values for the high affinity site corresponded well with the expected values for the H3 receptor. Antagonists fully displaced the binding of 5 nM [3H]-thioperamide w

Topics: Animals; Cerebral Cortex; Dose-Response Relationship, Drug; Histamine Antagonists; Imidazoles; Isothiuronium; Male; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Receptors, Histamine

The binding of thioperamide, a known H3-receptor antagonist, to rat plasma and proteins and its affinity for rat cerebral phospholipids are investigated. Thioperamide is strongly bound to plasma proteins (95-80% at plasma concentrations of 3.5-400 micrograms mL-1), and its binding can be resolved into two components a high-affinity, saturable component and a non-specific component. The drug has a high affinity for cerebral phospholipids, with a partition coefficient of approximately 100 (log K = 2.06 +/- 0.14), which should promote brain penetration and accumulation. Protein binding and cerebral phospholipid affinity can suggest the explanation of some differences reported in the literature on thioperamide distribution data: at low plasma concentrations of the drug, its protein binding (95% at 3.5 micrograms mL-1) can prevent brain accumulation, while at higher concentrations the free plasma fraction suddenly increases (> 10% at 18 micrograms mL-1) and it allows passive distribution to lipophilic tissues such as brain tissue.

Topics: Animals; Blood Proteins; Brain; Histamine Antagonists; Phospholipids; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

The social memory test was used so as to investigate whether brain histamine is involved in short-term memory. Histamine injected intracerebroventricularly (i.c.v.) decreased investigation time of a juvenile rat by an adult rat. A similar effect was elicited by i.c.v. administration of histidine. Compared with the control animals, rat pretreatment with alpha-fluoromethylhistidine (FMH), which inhibits neuronal synthesis of histamine, prolonged recognition time. The H3-receptor agonist immepip also prolonged investigation time, while the H3-antagonist thioperamide exerted the opposite effect. Treatment with histidine increased, while treatment with FMH decreased histamine levels in various brain regions. It is concluded that histamine released from histaminergic neurons facilitates short-term memory.

Topics: Animals; Behavior, Animal; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Imidazoles; Male; Memory, Short-Term; Methylhistidines; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Social Behavior; Time Factors

The aim of this study was to investigate the possible involvement of the histamine H3 receptor in control of exocrine pancreatic secretion from the guinea-pig. In in vitro experiments, the H3 receptor agonist (R)-alpha-methylhistamine (0.01-10 microM) elicited a concentration-dependent decrease in the release of alpha-amylase. (R)-alpha-Methylhistamine concentrations above 10 microM evoked a concentration-dependent increase in alpha-amylase secretion. Application of mepyramine (1 microM) partially blocked this increase. The H3 receptor antagonist thioperanide (1 microM) blocked the effects of (R)-alpha-methylhistamine below 10 microM. Histamine and (R)-alpha-methylhistamine attenuated both protein release elicited during electrical-field stimulation and the release of tritiated choline, and these effects were reversed by thioperamide. In an in vivo study, (R)-alpha-methylhistamine increased juice secretion and total protein content of the juice by 40%. Histamine H1 and H2 receptor antagonists blocked this increase and uncovered an attenuation of the secretory parameters (juice flow 28%, total protein content 44%). This attenuation was blocked by thioperamide. These observations suggest that stimulation of the histamine H3 receptor in the pancreas results in a decreased fluid and enzyme release by inhibition of acetylcholine release from intrinsic pancreatic nerves.

Topics: alpha-Amylases; Animals; Choline; Electric Stimulation; Female; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Pancreas; Piperidines; Pyrilamine; Receptors, Histamine H3; Tritium

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by spinally administered morphine, beta-endorphin and U50, 488H. The effects of intrathecal (i.t.) injections with cyproheptadine (a histamine-1 (H1) receptor antagonist), ranitidine (an H2 receptor antagonist), or thioperamide (an H3 receptor antagonist) injected i.t., on the antinociception induced by morphine, beta-endorphin or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide (U50, 488H) injected intrathecally (i.t.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (20 micrograms), ranitidine (20 micrograms), or thioperamide (20 micrograms) alone did not produce any antinociceptive effect. i.t. pretreatment with cyproheptadine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine or beta-endorphin, but not U50, 488H. In addition, i.t. pretreatment with ranitidine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine, beta-endorphin, or U50, 488H. Furthermore, the i.t. pretreatment with thioperamide attenuated the inhibition of the tail-flick response induced by beta-endorphin or U50, 488H, but not morphine, administered i.t. Our results indicate that spinal H1 receptors may be involved in the production of antinociception induced by spinally applied morphine or beta-endorphin- but not U50, 488H. Spinal H2 receptors appear to be involved in spinally administered morphine-, beta-endorphin- and U50, 488H-induced antinociception. Supraspinal histamine H3 receptors may be involved in the production of antinociception induced by supraspinally applied beta-endorphin or U50, 488H, but not morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cyproheptadine; Histamine H1 Antagonists; Histamine H2 Antagonists; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Pain; Pain Measurement; Piperidines; Pyrrolidines; Ranitidine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Spinal Cord

Histamine may play a role in synchronizing endogenous circadian rhythms with exogenous photic cues. Direct application of histamine to the suprachiasmatic nucleus, the site of the mammalian circadian pacemaker, phase shifts the circadian rhythm in neural activity [7]. Intraventricular injections of histamine also phase shift circadian rhythms [14]. The magnitude and direction of the phase shifting effects of histamine depend on circadian phase in a manner similar to light [7,14]. Depletion of brain histamine levels by inhibition of histamine synthesis reduces phase shifts to light [10].

Topics: Animals; Benzothiazoles; Cimetidine; Circadian Rhythm; Cricetinae; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Mesocricetus; Phenoxypropanolamines; Photoperiod; Piperidines; Pyrilamine; Receptors, Histamine H3; Thiazoles

Following tacrine administration i.p. to mice, the histamine N-methyltransferase activity of brain homogenates was more potently inhibited than the acetylcholinesterase activity (ID50 of 5.3 mg/kg vs. 13.6 mg/kg). The formation of the metabolite, tele-methylhistamine, in brain of mice treated with an histamine H3 receptor antagonist was abolished by tacrine with an ID50 as low as 1.2 +/- 0.4 mg/kg. The participation of histamine in the actions of tacrine and the relevance of histamine H3 receptor antagonists in Alzheimer's disease are suggested.

Topics: Animals; Cerebral Cortex; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Histamine Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mice; Nootropic Agents; Piperidines; Tacrine

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

Histaminergic H3 receptor antagonists stimulate neuronal histamine release and could consequently have a number of physiological effects in the brain. The effects of H3 receptor blockade, induced by systemically administered thioperamide, were assessed on the frontal cortex electroencephalographic (EEG) properties in freely behaving rats. The relationship of EEG activity variables to endogenous brain histaminergic markers was also examined, both in controls and in portocaval anastomosis (PCA)-operated rats (which show increased levels of brain histamine and t-methylhistamine). Thioperamide reduced the incidence of thalamus-regulated EEG spindles, while it slightly increased their amplitude. It furthermore reduced the spectral power of low-frequency (1.5-5Hz) EEG, which effect was equally distributed over the spindle and non-spindle EEG states. These EEG effects were accompanied by increased motor activity of the animals. Both the low-frequency EEG activity and spindle incidence correlated inversely with the histamine level of the brain (hypothalamus and cerebellum excluded) while t-methylhistamine level correlated with the degree of thioperamide-induced reduction of slow-wave EEG activity. The present results provide evidence for the involvement of endogenous brain histamine level, histamine release (as assessed by t-methylhistamine level) and H3 receptors in the histaminergic regulation of neocortical synchronization patterns assumed to be linked to arousal control.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Electroencephalography; Histamine; Histamine Antagonists; Light; Male; Motor Activity; Organ Size; Piperidines; Portacaval Shunt, Surgical; Rats; Rats, Wistar

We investigated the brain penetration of the histamine H3 receptor antagonists thioperamide and clobenpropit using ex vivo [125I]iodophenpropit binding. Homogenates of the rat cortex, striatum and mouse whole brain were prepared 1 h after subcutaneous injection of the H3 antagonists and incubated with [125I]iodophenpropit, a radiolabeled H3 receptor antagonist, to determine the H3 receptor occupancy. Specific [125I]iodophenpropit binding to the rat cortex and striatum was inhibited by thioperamide with IC30 values of 1.0 and 1.5 mg/kg, respectively. Clobenpropit also inhibited [125I]iodophenpropit binding, but was less potent (IC30: 18 and 19 mg/kg in the rat cortex and striatum, respectively) than thioperamide. Similar results were obtained in experiments with mouse whole brain (3.5 and 13 mg/kg for thioperamide and clobenpropit), indicating that there is no important species differences in the brain penetration of these drugs between rats and mice. These findings suggest that after peripheral injection both in rat and mouse thioperamide penetrates the blood-brain barrier more efficiently compared to clobenpropit.

Topics: Animals; Brain; Cerebral Cortex; Corpus Striatum; Histamine Antagonists; Imidazoles; Iodine Radioisotopes; Isothiuronium; Male; Mice; Mice, Inbred BALB C; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Thiourea

Involvement of histamine receptors and hypothalamic and hippocampal histamine in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by vasopressin (AVP) was investigated in conscious rats. The HPA activity was assessed by measuring serum corticosterone levels. One hour after administration AVP, (5 micrograms/kg) given i.p. significantly raised the serum corticosterone and hippocampal histamine levels, while the hypothalamic histamine content was not affected. Pretreatment with the inhibitor of the brain histamine synthesis alpha-fluoromethylhistidine (alpha-FMH) (50 mg/kg i.p.) considerably reduced both the AVP-elicited serum corticosterone response and the hypothalamic and hippocampal histamine levels. The histamine H1- and H2-receptor-antagonists mepyramine (0.01 mg/kg) and ranitidine (0.1 mg/kg), given ip 15 min prior to AVP, significantly impaired the AVP-induced rise in the serum corticosterone level and totally abolished the AVP-elicited increase in the histamine content in the hippocampus; moreover mepyramine significantly lowered this content in hypothalamus. Pretreatment with the histamine H3-receptor antagonist thioperamide (5 mg/kg i.p.) also significantly decreased the AVP-elicited corticosterone response, but did not alter the histamine content in either brain structure examined. These results indicate that central histamine H1-, H20 and H3-receptors significantly mediate the stimulatory action of AVP on the pituitary-adrenocortical axis. Hippocampal histamine may be involved in mediation of the AVP-induced effect via H1- and H2-receptors. The inhibitory effect of thioperamide seems to be located directly at non H3-intracellular sites of the pituitary-adrenocortical axis.

Topics: Adrenocorticotropic Hormone; Animals; Arginine Vasopressin; Corticosterone; Enzyme Inhibitors; Hippocampus; Histamine; Histamine Antagonists; Histidine Decarboxylase; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Methylhistidines; Piperidines; Pituitary-Adrenal System; Rats; Rats, Wistar; Receptors, Histamine

To study the histamine H3 receptors mediated inhibition of norepinephrine (NE) release from cardiac sympathetic terminals of guinea pig isolated atria.. Release of NE induced by electric field stimulation (50 mA, 5 ms) in the bath solution was measured by HPLC-ECD.. The release of NE caused by field stimulation was attenuated by (R)-alpha-methyl-histamine (alpha-MeHA, 0.1 nmol.L-1(-10) mumol.L-1) in a concentration-dependent manner. Thioperamide concentration-dependently antagonized the inhibition of alpha-MeHA. Blockade of H1, H2, alpha 2, beta 2-receptors failed to prevent the inhibitory effect of alpha-MeHA. Thioperamide (1 nmol.L-1(-10) mumol.L-1), when used alone, concentration-dependently facilitated the release of NE evoked by field stimulation.. The presynaptic histamine H3-receptors inhibited the NE release from cardiac sympathetic terminals.

Topics: Adrenergic Fibers; Animals; Dose-Response Relationship, Drug; Female; Guinea Pigs; Heart Atria; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Norepinephrine; Piperidines; Receptors, Histamine H3; Sympathetic Nervous System

The ability of (R)-alpha-methylhistamine, the selective agonist of histamine H3 receptors, to reduce ethanol-induced gastric damage was examined in the rat. (R)-alpha-methylhistamine (1-100 mg/kg intragastrically) caused a dose-related reduction in the amount of damage produced by ethanol. This protective effect was not shared by the S enantiomer of alpha-methylhistamine. Thioperamide, selective H3 receptor antagonist, inhibited the protective effect of 10 but not 100 mg/kg of (R)-alpha-methylhistamine. Pretreatment with (R)-alpha-methylhistamine, 100 mg/kg i.g., resulted in a significant increase in the thickness of adherent mucus gel layer, which may contribute to the protective action of the compound.

Topics: Analysis of Variance; Animals; Drug Interactions; Ethanol; Gastric Mucosa; Histamine Agonists; Male; Methylhistamines; Mucus; Piperidines; Rats; Rats, Wistar; Surface Properties; Time Factors

We examined the effects of thioperamide and (R)-alpha-methylhistamine, a histamine H3-receptor antagonist and an agonist, respectively, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice. Thioperamide alone slightly improved the learning deficit induced by scopolamine, and pretreatment with zolantidine, a histamine H2-receptor antagonist, significantly enhanced the effect of thioperamide in this test. (R)-alpha-Methylhistamine, pyrilamine, ketotifen, terfenadine, and zolantidine alone at the doses tested had no effect. Moreover, the improvement by thioperamide plus zolantidine was antagonized by pretreatment with histamine H1-receptor antagonists such as pyrilamine or ketotifen, but not by terfenadine. Thus, thioperamide improved the scopolamine-induced learning deficit through central histamine H1 receptors in mice. The present results supported the hypothesis that histamine may play an important role in learning and memory.

Topics: Animals; Benzothiazoles; Histamine; Histamine Antagonists; Male; Maze Learning; Mice; Mice, Inbred ICR; Phenoxypropanolamines; Piperidines; Scopolamine; Thiazoles

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Topics: Administration, Oral; Aerosols; Albuterol; Analysis of Variance; Animals; Antitussive Agents; Capsaicin; Chlorpheniramine; Cimetidine; Codeine; Cough; Drug Hypersensitivity; Guinea Pigs; Hexamethonium; Histamine Antagonists; Indomethacin; Injections, Subcutaneous; Ipratropium; Loratadine; Male; Ovalbumin; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2

The involvement of the histamine H3 receptor in the regulation of substance P release in neurogenic inflammation was studied by using rat hindpaw skin. R-(-)-alpha-Methylhistamine, a specific histamine H3 receptor agonist, significantly inhibited the increased vascular permeability induced by antidromic electrical stimulation of the sciatic nerve in a dose-dependent manner at doses of 0.5-3 mg/kg (i.v.), and thioperamide (2 mg/kg i.p.), a specific histamine H3 receptor antagonist, prevented the inhibitory effect of R-(-)-alpha-methylhistamine. The antidromic stimulation also caused a significant increase in immunoreactive substance P release in the subcutaneous (s.c.) perfusate in the rat hindpaw. R-(-)-alpha-Methylhistamine (0.25-2 mg/kg) dose dependently inhibited the increase in release of immunoreactive substance P, and thioperamide (2 mg/mg i.p.) antagonized it. Perfusion of histamine (10(-3) M) elicited a significant increase of immunoreactive substance P release in the perfusate, which was reduced by R-(-)-alpha-methylhistamine and the antagonism of thioperamide was also observed. Histamine (in the presence of histamine H1 and H2 receptor antagonists) had an inhibitory effect on the electrically evoked release of immunoreactive substance P. These results strongly support the hypothesis that histamine regulates substance P release via prejunctional histamine H3 receptors that are located on peripheral endings of sensory nerves.

Topics: Animals; Capillary Permeability; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Nerve Endings; Neurons, Afferent; Perfusion; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Receptors, Presynaptic; Sciatic Nerve; Stimulation, Chemical; Substance P

We examined possible interactions between neuroleptics and the histamine H3 receptor and found an interaction of clozapine with this receptor. In competition binding experiments, using the H3 antagonist, [125I]-iodophenpropit, we observed a Ki of 236 +/- 87 nM. Functionally, clozapine was studied on the H3-mediated inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from rat brain cortex slices. Clozapine acts as an antagonist with an apparent KB value of 79.5 nM.

Topics: Animals; Binding, Competitive; Cerebral Cortex; Clozapine; Haloperidol; Histamine Antagonists; Histamine Release; Imidazoles; Isothiuronium; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3

The secretion and function of antral histamine are not known. The aims of this study were to characterize the mechanisms of histamine release from the gastric antrum of humans, dogs, and rats and to determine whether histamine can influence the secretion of somatostatin and gastrin.. Somatostatin, gastrin, and histamine secretion from superfused antral segments was measured using radioimmunoassay.. Superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased gastrin and histamine secretion in all three species; superfusion with (r)-alpha-methylhistamine (H3 agonist) had the opposite effect. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion, which in turn regulates gastrin secretion. Superfusion with somatostatin antibody increased histamine secretion; the increase was not affected by the gastrin antagonist L-365,260, implying that it was not mediated by the concurrent increase in gastrin but by suppression of an inhibitory pathway linking somatostatin and histamine. Superfusion with methacholine alone and in the presence of either the H3 agonist or antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine.. Antral histamine in humans, dogs, and rats is linked to antral somatostatin via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Topics: Animals; Benzodiazepinones; Dogs; Gastric Mucosa; Gastrins; Histamine Antagonists; Histamine Release; Humans; In Vitro Techniques; Methacholine Chloride; Methylhistamines; Neural Pathways; Phenylurea Compounds; Piperidines; Pyloric Antrum; Rats; Somatostatin

1. The effect of central H3 histamine receptor activation on gastric acid and pepsin production has been investigated in pylorus-ligated rats. 2. Intracerebroventricular injections (i.c.v.) of the selective H3 agonist, R-alpha-methylhistamine (0.5-50 nmol per rat) caused a dose-dependent inhibition of gastric acid secretion while intravenous administration (5-500 nmol per rat) was completely ineffective. 3. I.c.v. microinjections of mepyramine, tiotidine and thioperamide (51 nmol per rat), selective antagonists at H1-, H2- and H3-sites respectively, failed to modify the acid secretory response to pylorus ligation. 4. The antisecretory effect of R-alpha-methylhistamine (5 nmol per rat, i.c.v.) was selectively prevented by the H3-blocker, thioperamide (51 nmol per rat, i.c.v.), mepyramine and tiotidine pretreatment being completely inactive. 5. Unlike acid secretion, pepsin production was not significantly affected by all the tested compounds. 6. These findings provide the first pharmacological evidence that the activation of central H3 histamine receptors exerts a negative control in the regulation of gastric acid secretion in conscious pylorus-ligated rats.

Topics: Animals; Cimetidine; Female; Gastric Acid; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; Injections, Intraventricular; Methylhistamines; Piperidines; Pylorus; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

1. The pharmacological properties and location of H3 receptors modulating acetylcholine release have been investigated in non-superfused slices and synaptosomes of rat entorhinal cortex preloaded with [3H]-choline. 2. (R)alpha-methylhistamine, an H3-receptor agonist, potently inhibited the K(+)-evoked tritium release from slices, an effect antagonized by thioperamide, an H3-receptor antagonist, with nanomolar potency. 3. The K(+)-evoked tritium release from synaptosomes remained unaltered in the presence of the potent and selective H3-receptor agonists, imetit and (R)alpha-methylhistamine, suggesting that H3 receptors modulating acetylcholine release are not presynaptically located on cholinergic nerve terminals. 4. Phenylbutanoylhistamine and phenylpropylhistamine, two H3-receptor antagonists of moderate potency, failed to antagonize the inhibitory effects of (R)alpha-methylhistamine observed in slices. Unexpectedly, both compounds when used alone, inhibited tritium release from slices and synaptosomes with micromolar potency and to the same extent (by approximately 50% when added at a final concentration of 200 microM). This inhibitory effect did not involve H1, H2 or H3 receptors and was not mediated by an unknown histamine receptor site, since histamine used at a high concentration neither reproduced nor antagonized the effect of phenylbutanoylhistamine. It remained unaltered in the presence of scopolamine and was neither mimicked nor antagonized by vasoactive intestinal peptide, previously shown to be colocalized with acetylcholine in some neurones. 5. It is concluded that acetylcholine release in rat entorhinal cortex is modulated by H3 receptors presumably not located on cholinergic axon terminals. It remains to be established whether these H3 receptors belong to a receptor subtype different from those previously described since the potency ofphenylbutanoylhistamine and phenylpropylhistamine as H3-receptor antagonists was probably greatly underestimated by additional properties of both drugs.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Entorhinal Cortex; Histamine Antagonists; Male; Piperidines; Potassium; Rats; Rats, Wistar; Receptors, Histamine H3; Synaptosomes; Tritium

The effect of thioperamide, a histamine H3 receptor antagonist, on learning and memory was studied in the senescence-accelerated mice-prone strain (SAM-P/8) and normal-rate aging strain (SAM-R/1). In a passive avoidance test, SAM-P/8 mice of 12 months showed significant impairment of learning and memory compared with SAM-R/1 mice of the same age. Thioperamide significantly improved the response latency in SAM-P/8 mice when injected intraperitoneally at a dose of 15 mg/kg. The histidine decarboxylase (HDC) activity in the forebrain was significantly lower in SAM-P/8 mice than in SAM-R/1 mice. Thioperamide administration significantly potentiated HDC activity in the forebrain of SAM-P/8 mice as well as improving learning and memory. These results suggest that central histaminergic neurons may be involved in learning and memory impairment of SAM-P/8 mice, although other possibilities are not ruled out.

Topics: Aging; Animals; Avoidance Learning; Histamine Antagonists; Histidine Decarboxylase; Male; Mice; Mice, Inbred Strains; Piperidines

Thioperamide, an H3-receptor antagonist that enhances endogenous histamine release, induced c-fos mRNA expression and Fos-like immunoreactivity in magnocellular neurones of rat supraoptic and paraventricular nuclei. This response was prevented as a result of blockade of the H1 receptor, indicating that endogenous histamine is able to activate these magnocellular neurones via stimulation of this receptor.

Topics: Animals; Base Sequence; Gene Expression Regulation; Genes, fos; Histamine; Histamine Antagonists; Immunohistochemistry; In Situ Hybridization; Male; Molecular Sequence Data; Neurons; Paraventricular Hypothalamic Nucleus; Piperidines; Rats; Rats, Wistar; RNA Probes; RNA, Messenger; Supraoptic Nucleus

This study examined the gastroprotective effect of (R)-alpha-methylhistamine (MHA), a selective agonist of histamine H3 receptors. Gastric lesions were induced in the rat by administering absolute ethanol in a volume of 1 ml. Stomachs were removed 1 h later and lesions evaluated both macroscopically and histologically. MHA dose-dependently inhibited ethanol-induced lesions in the range 1-100 mg/kg both by the intragastric and intraperitoneal route. Histological findings indicated that the number of mucous granules in surface and neck cells was increased and the process of reepithelialization was rapidly promoted by MHA. Thioperamide, at 10 mg/kg, inhibited the protective effect of 10 but not of 100 mg/kg of MHA. Larger doses of thioperamide could not be tested because of an interaction with ethanol causing central nervous system effects. Famotidine and indomethacin pretreatment only partially counteracted the MHA effect. The results indicate that MHA is highly effective in preventing ethanol-induced lesions but the exact mechanism is still uncertain.

Topics: Animals; Ethanol; Famotidine; Gastric Mucosa; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H3-receptors inhibits norepinephrine release, we searched for the presence of H3-receptors directly in sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human atria. Norepinephrine was released by depolarization with K+. The presence of H3-receptors was ascertained because the selective H3-receptor agonists (R) alpha-methylhistamine and imetit reduced norepinephrine release, and the specific H3-receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca(2+)-channel blocker omega-conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H3-receptors was obtained by showing that transmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranolol and attenuated in a concentration-dependent manner by (R) alpha-methylhistamine. Also, thioperamide antagonized the effect of (R) alpha-methylhistamine. Our findings are the first demonstration that H3-receptors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine release. Since myocardial ischemia causes intracardiac histamine release, H3-receptor-induced attenuation of sympathetic neurotransmission may be clinically relevant.

Topics: Cell Separation; Electric Stimulation; Exocytosis; Heart; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; In Vitro Techniques; Indoles; Methylhistamines; Myocardial Ischemia; Myocardium; Norepinephrine; Piperidines; Protein Kinase C; Receptors, Histamine H3; Synaptosomes; Thiourea

Widespread clinical use of H2 antagonists for peptic ulcer disease has been associated with reports of impotence. Histamine is a vasoactive amine which is endogenously produced in many organs including the penis. To date, 3 histamine receptor subtypes (H1, H2 and H3) have been identified. However, the role and function of histamine in the corpus cavernosal physiology are poorly understood. This study evaluates the in vitro functional characteristics of the 3 histamine receptor subtypes in the isolated corpus cavernosal strips from New Zealand White rabbits. The isometric responses to histamine and specific histamine receptor subtype agonists were assessed, following cyclooxygenase (indomethacin, 10(-5) M.), adrenergic (guanethidine, 5 x 10(-6) M.) and cholinergic (atropine, 5 x 10(-6) M.) blockade, at resting tension and after submaximal precontraction with norepinephrine (NE, 2 x 10(-5) M.). Histamine (10(-8) M. to 10(-3) M.) produced concentration-dependent contraction from basal and precontracted states and did not relax precontracted tissue. The H1 agonist, 2-(2-thiazolyl)ethylamine (10(-8) M. to 10(-3) M.), produced a contractile response from both basal and precontracted states, while the corporal tissue did not respond to either dimaprit, an H2 agonist (10(-8) M. to 10(-5) M.) or R(-)-alpha-methyl-histamine, an H3 agonist (10(-8) M. to 10(-5) M.). The response to histamine was progressively attenuated by an H1 antagonist (mepyramine; 10(-8) M. to 10(-5) M.), while neither an H2 antagonist (cimetidine; 10(-4)M.) nor an H3 antagonist (thioperamide; 10(-4)M.) had any inhibitory effects. H1 antagonism enhanced relaxation induced by electrical field stimulation (neurally mediated). Such relaxation increased after preincubation with 10(-6) M. or greater of mepyramine (p < 0.05). This study suggests that the principal histamine receptor subtype that mediates smooth muscle cell contraction in the corpus cavernosum is the H1 subtype. Since histamine H1 receptor antagonism increased NANC neurally mediated corporal relaxation, it possesses potential as an intracavernosal pharmacotherapeutic agent for the treatment of erectile dysfunction. This study, therefore, strongly indicates that H2 receptor antagonists are unlikely to have direct effects on penile erection.

Topics: Acetylcholine; Animals; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Papaverine; Penis; Piperidines; Pyrilamine; Rabbits; Receptors, Histamine; Thiazoles

1. Conflicting reports in the literature over heterogeneity (West et al., 1990) or homogeneity (Arrange et al., 1990) of histamine H3-receptor binding sites may be attributed to the use of different incubation conditions. In the present study we have investigated the extent to which the binding of H3-receptor ligands to rat cerebral cortical membranes can be modified by both sodium ions and guanine nucleotides. 2. The H3-selective antagonist, thioperamide, discriminated between two specific binding sites for [3H]-N alpha-methylhistamine (IC50 1 = 2.75 +/- 0.87 nM, IC50 2 101.6 +/- 12.0 nM, % site 1 = 24 +/- 2%) in 50 mM Tris HCl buffer, but showed homogeneity of binding in 50 mM Na/K phosphate buffer. 3. Sodium ions markedly altered the binding characteristics of thioperamide (i.e. heterogeneity was lost and IC50 value shifted towards the high affinity site). The competition curves for a second H3-antagonist, clobenpropit and the H3-agonist N alpha-methylhistamine however, were unaltered in the presence of sodium ions. 4. Guanylnucleotides displaced only 60% of specific [3H]-N alpha- methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. 5. These data suggest that the H3-receptor can exist in different conformations for which thioperamide, but not N alpha-methylhistamine and clobenpropit, show differential affinity. 6. The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3-receptor antagonism by thioperamide, are discussed.

Topics: Animals; Cerebral Cortex; Guanine Nucleotides; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Male; Membranes; Methylhistamines; Piperidines; Rats; Receptors, Histamine H3; Sodium; Thiourea

Topics: Adrenocorticotropic Hormone; Animals; Histamine Antagonists; Histamine Release; Male; Piperidines; Portacaval Shunt, Surgical; Prolactin; Rats; Rats, Wistar

We previously reported evidence for H3-receptor inhibition of cholinergic stimulation of acid secretion by isolated rabbit gastric glands. Because this inhibition was unsensitive to H2 antagonists, we postulated that the parietal cell should bear a H3-receptor. In the present study, we investigated the effects of M1-M3 muscarinic receptors antagonists on carbachol- and thioperamide-induced acid secretion (14CAP uptake) by isolated rabbit gastric glands. Furthermore, we examined whether H3-receptor ligands could affect [3H]-N-methylscopolamine binding to the isolated rabbit parietal cells. Both carbachol and thioperamide concentration-dependently stimulated 14CAP uptake in the glands with maximal responses being achieved for 100 microM and 0.1 microM, respectively. These stimulations were concentration-dependently inhibited by the H3-receptor agonists R(alpha)-methylhistamine and imetit. Maximal inhibitions did not exceed 60% for 1 microM. The muscarinic receptor antagonists, hexa-sila-difenidol p-fluoro analog (M3), pirenzepine (M1) and gallamine (M2) inhibited carbachol-induced 14CAP uptake with IC50 of 50 nM, 10 microM and >> 100 microM, respectively. Thioperamide-induced 14CAP uptake was also inhibited by hexa-sila-difenidol p-fluoro analog and pirenzepine with IC50 of 90 nM and 12 microM, respectively; whereas gallamine had no effect. [3H]-N-methylscopolamine binding to isolated parietal cells was inhibited by atropine and pFHHSiD with IC50 of 15 nM and 132 nM, respectively. Neither R(alpha)-MeHA nor thioperamide did affect this binding although a H3-receptor inhibitory effect was observed on carbachol-induced 14CAP uptake by the cells. These data support that H3-receptor activation inhibits M3-mediated cholinergic stimulation of acid secretion through mechanisms operating downstream to the receptors sites.

Topics: Animals; Carbachol; Cholinergic Antagonists; Gastric Acid; Gastric Fundus; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Methylhistamines; Muscarinic Antagonists; N-Methylscopolamine; Piperidines; Rabbits; Ranitidine; Receptors, Histamine H3; Receptors, Muscarinic; Scopolamine Derivatives

Considerable evidence has shown that both cholinergic and histaminergic neurons in the brain may act to facilitate processes of cortical activation that occur during wakefulness. In the present study, the potential influence of histaminergic neurons upon cholinergic neurons of the basal forebrain was investigated in guinea-pig basal forebrain slices. We found that electrophysiologically identified and immunohistochemically verified cholinergic neurons of the nucleus basalis were depolarized and excited by histamine, as manifested by an increase in tonic firing. The depolarization was associated with an increase in membrane input resistance. The effect of histamine persisted in the presence of either tetrodotoxin or a high-magnesium/low-calcium solution, indicating that it is postsynaptic. By a process of elimination, the participation in this response of the three described histamine receptors was examined. Involvement of H3 receptors was excluded on the basis that the H3 agonist (R)-alpha-methyl-histamine had no direct effect, and the H3 antagonist, thioperamide, did not block the effect of histamine. In contrast, the presence of a small response to impromidine, a selective agonist of H2 receptors, and the partial block of the response to histamine by the H2 receptor antagonist, cimetidine, indicated the participation of H2 receptors. Finally, the complete elimination of histamine's effect occurred when low doses of the H1 antagonist, mepyramine, were added to the H2 antagonist, cimetidine, indicating the involvement and predominance of H1 receptors in the response. Our data thus suggest that histamine excites nucleus basalis cholinergic neurons by a concomitant activation of H1 and H2 receptors. Histaminergic tuberomammillary neurons may accordingly facilitate tonic firing of cholinergic neurons during wakefulness. Cholinergic basalis neurons could thus act in tandem with histaminergic neurons during periods of arousal to collectively promote widespread cortical activation.

Topics: Action Potentials; Animals; Cholinergic Fibers; Cimetidine; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Antagonists; In Vitro Techniques; Neurons; Piperidines; Substantia Innominata

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. The interaction with the 5-HT3 receptor was not restricted to IPP or thioperamide, but was alsofound with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belongingto the same chemical class of IPP, also interacted with the 5-HT3 receptor (Ki = 240 +/- 40 nM). In contrast,histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor.7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in apD2 value of 4.72 +/- 0.03 (n = 9). The contractions were antagon

Topics: Animals; Binding, Competitive; Cerebral Cortex; Guinea Pigs; Histamine Agents; Histamine Antagonists; Ileum; Imidazoles; In Vitro Techniques; Isothiuronium; Jejunum; Male; Muscle Contraction; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Reflex; Serotonin Antagonists

A role for endogenous histamine and its H3 receptor subtype for mediating drinking elicited by eating was examined in adult male Sprague-Dawley rats. The i.p. injection of the H3 agonist R-alpha-methylhistamine (Ramh, 2.5 mg/kg) shortened the latency to initiate drinking and increased 1-h water intake in nondeprived rats freely eating pellets and drinking water. The ICV injection (through a surgically implanted chronic cannula) of 10 micrograms Ramh increased water intake; this Ramh-induced drinking was abolished by previous ICV injection of the H3 antagonist thioperamide (Th, 60 micrograms). For rats drinking and eating after 24-h food deprivation, s.c. Th inhibited drinking behavior: for example, 10 mg/kg Th s.c. delayed the latency to initiate drinking and inhibited 1-h water intake without inhibition of food intake. In contrast, 60 micrograms Th ICV failed to inhibit food-related drinking in rats eating after food deprivation. For nondeprived rats eating a small cracker, 10 mg/kg Th s.c. delayed the latency to initiate drinking and abolished water intake without effect of eating, and 60 micrograms Th ICV had similar effects upon drinking elicited by ingestion of cracker. The IG infusion (through a surgically implanted gastric catheter) of 2 ml 600 or 900 mOsm/kg NaCl, a treatment that is subthreshold for increase in systemic plasma osmolality at the initiation of drinking, elicited drinking that was abolished by 10 mg/kg Th s.c. and attenuated by 60 micrograms Th ICV. The IG infusion of 2 ml 1800 mOsm/kg NaCl, a treatment that is above threshold for increase in systemic plasma osmolality, elicited drinking that was attenuated by 10 mg/kg s.c. or 60 micrograms Th ICV. These results demonstrate that peripheral and central H3 receptors for histamine have a role in drinking elicited by eating and the postprandial gastrointestinal osmotic consequences of eating. These findings extend the evidence demonstrating a histaminergic contribution to food-related drinking in rats.

Topics: Animals; Behavior, Animal; Drinking; Eating; Histamine Antagonists; Male; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Histamine H3

The aim of the present paper was to summarize histamine-mediated repair of rat intestinal mucosa. To evaluate intestinal repair, we examined lipid transport (an index of intestinal mucosal function) after 15 minutes occlusion of the superior mesenteric artery. Rats were pretreated with alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase, a synthesizing enzyme of histamine), H1-receptor antagonist (chlorpheniramine maleate), H2-antagonist (cimetidine), or H3-antagonist (thioperamide) before ischemia-reperfusion (I/R). Lipid transport to rat mesenteric lymph decreased significantly 24 hours after I/R in all groups tested compared to sham-treated rats. Lipid transport was restored 48 hours after I/R in the vehicle-pretreated control group. Lipid transport was not restored to the control level 48 hours after I/R in rats pretreated with H1-antagonist and a suicide inhibitor of histidine decarboxylase. In contrast, intestinal function was restored to the control level 48 hours after I/R in rats pretreated with H2- and H3-antagonists. These results support our previous findings that newly formed histamine after I/R plays an important role in mucosal recovery through H1-receptors.

Topics: Animals; Biological Transport; Chlorpheniramine; Cimetidine; Enzyme Inhibitors; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine Decarboxylase; Intestinal Mucosa; Ischemia; Lipid Metabolism; Lymph; Male; Methylhistidines; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion

The effects of an H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in rat hypothalamus were studied in vitro. Thioperamide was more potent in inhibiting MAO-B than MAO-A activity; MAO-B activity in rat hypothalamic homogenates was competitively inhibited by thioperamide with a Ki value of 175 micronM. From this in vitro experiment, the conversion of N-telemethylhistamine to N-tele-methylimidazoleacetic acid may be inhibited by thioperamide, suggesting that thioperamide may affect the regulation of histamine metabolism within histaminergic neurons. In contrast with the results obtained with thioperamide, alpha-MeHA inhibited MAO-A more potently than MAO-B activity; the Ki values for MAO-A and -B of hypothalamic homogenates were estimated to be 1.1 and 3.3 mM, respectively. The weak inhibitory effect of alpha-MeHA for MAO-B does not seem to be a major cause of changes in N-tele-methylhistamine concentrations.

Topics: Animals; Brain; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Monoamine Oxidase; Piperidines; Rats; Rats, Sprague-Dawley

We characterized the histamine H3 receptors involved in the modulation of electrical field stimulated neurogenic contraction of guinea pig pulmonary artery sympathetic, and guinea pig ileum parasympathetic preparations. Simultaneous measures of electrical field stimulation-evoked 3H overflow and tension in [3H]norepinephrine-loaded pulmonary artery were sensitive to tetrodotoxin (300 nM) and insensitive to hexamethonium (100 microM). Only the contractile response was inhibited by prazosin (100 nM). (R)-alpha-Methylhistamine's inhibition of the pulmonary artery contraction and 3H overflow were dose-dependently antagonized by thioperamide (30-100 nM). (R)-alpha-Methylhistamine also inhibited the neurogenic contractions of the isolated ileum (pD2 = 8.2). In the pulmonary artery, the relative potency of the histamine H3 receptor antagonists vs. (R)-alpha-methylhistamine inhibition of neurogenic contractions (pD2 = 7.1) was thioperamide (pA2 = 8.6 +/- 0.1) > burimamide (pA2 = 7.6 +/- 0.2) > impromidine (pA2 = 6.9 +/- 0.02). Similarly, the relative potency of histamine H3 receptor antagonists in the isolated ileum was thioperamide > burimamide > or = impromidine, with pA2 estimates of 8.7 +/- 0.1, 7.3 +/- 0.1 and 7.1 +/- 0.1, respectively. Antagonist potencies suggest a predominant histamine H3A-like receptor population on postganglionic sympathetic neurons innervating the pulmonary artery and parasympathetic neurons innervating the ileum longitudinal muscle.

Topics: Animals; Brain Chemistry; Electric Stimulation; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Ileum; In Vitro Techniques; Methylhistamines; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Norepinephrine; Piperidines; Pulmonary Artery; Receptors, Histamine H3; Vasoconstrictor Agents

We investigated the effects of thioperamide, a histamine H3-receptor antagonist, on a scopolamine-induced learning deficit in the step-through passive avoidance test in mice, and on contents of acetylcholine and choline in the brain. In a behavioral study, thioperamide (20 mg/kg) alone slightly ameliorated scopolamine-induced learning deficit, and pretreatment with zolantidine, a histamine H2-receptor antagonist, significantly enhanced the ameliorating effect of thioperamide. This enhanced ameliorating effect of thioperamide was antagonized by pyrilamine, a histamine H1-receptor antagonist and (R)-alpha-methylhistamine, a histamine H3-receptor agonist, suggesting that thioperamide showed the ameliorating effect via histamine H3 receptors and/or histamine H1 receptors. In the biochemical study, thioperamide (20 mg/kg) in combination with zolantidine (20 mg/kg) significantly increased contents of choline in most of brain regions. These findings suggest that there is a close relationship between histaminergic and cholinergic systems in the brain, and that the histaminergic system may play certain important roles in learning and memory.

Topics: Acetylcholine; Animals; Avoidance Learning; Brain Chemistry; Choline; Histamine Antagonists; Male; Memory; Mice; Mice, Inbred ICR; Parasympathetic Nervous System; Parasympatholytics; Piperidines; Rats; Scopolamine

Previous studies have shown that antinociceptive doses of systemic morphine increase extracellular histamine (HA) levels in the rat periaqueductal gray (PAG), although the cellular origin of basal and morphine-induced HA release in the PAG is unknown. Treatment with alpha-fluoromethylhistidine (FMH; 100 mg/kg, i.p.), the irreversible inhibitor of histidine decarboxylase, decreased basal HA release by a maximum of 80% and prevented morphine-induced HA release in the PAG. In addition, perfusion of this area with the sodium channel blocker tetrodotoxin (10(-6) M) decreased basal HA release by a maximum of 57% from baseline levels. When the perfusion medium was modified by substitution of magnesium for calcium, extracellular HA levels in the PAG decreased by a maximum of 72%, and morphine-induced HA release was prevented. Thioperamide (5 mg/kg, i.p.), an H3 antagonist, increased HA release in the PAG to a maximum of 249% within the first 30-60-min period. Taken together, these results suggest that basal and morphine-induced HA release in the rat PAG have a neuronal origin.

Topics: Animals; Anticonvulsants; Histamine Release; Histidine Decarboxylase; Male; Methylhistidines; Morphine; Periaqueductal Gray; Piperidines; Rats; Rats, Sprague-Dawley; Tetrodotoxin

Previously, we showed that an elevated production of histamine promotes the healing of injured intestinal mucosa after ischemia-reperfusion. The aim of the present study was to determine whether histamine-mediated repair of the intestinal mucosa after ischemia-reperfusion involves the engagement of H1 or H2 receptors.. The superior mesenteric artery was occluded for 15 minutes followed by reperfusion, and H1- or H2-receptor antagonists were infused intraduodenally. After ischemia-reperfusion, ornithine decarboxylase activity in the jejunal mucosa and lipid transport to mesenteric lymph were examined.. In jejunal mucosa, ornithine decarboxylase activity markedly increased at 6 hours after reperfusion and remained elevated at 48 hours. The ischemia-reperfusion-induced increase in ornithine decarboxylase activity was attenuated (in a dose-dependent manner) by an H1-receptor antagonist (chlorpheniramine maleate) but not by an H2 antagonist (cimetidine). Intraperitoneal injection of an H3 antagonist (thioperamide) increased histamine output in mesenteric lymph and stimulated intestinal ornithine decarboxylase activity. Transport of dietary lipid into mesenteric lymph was depressed 24 hours after an ischemic insult, yet it returned to the normal level 48 hours after ischemia-reperfusion. The recovery of the lipid transport normally observed at 48 hours after ischemia-reperfusion was attenuated by the H1 antagonist.. The beneficial effects of histamine on the repair of intestinal mucosa after ischemia-reperfusion results from the engagement and activation of the H1 receptor.

Topics: Animals; Biological Transport; Chlorpheniramine; Cimetidine; Dietary Fats; Histamine Antagonists; Histamine Release; Intestinal Mucosa; Intestines; Lymph; Male; Ornithine Decarboxylase; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Reperfusion Injury

To investigate the modulation of histamine release by autoreceptors and heteroreceptors, the rat anterior hypothalamus was superfused through a push-pull cannula with agonists or antagonists of histamine and acetylcholine muscarinic receptors. Superfusion with the H3 receptor agonist (R)-alpha-methylhistamine inhibited, while superfusion with thioperamide (H3 antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M1, M2, M3 agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M1, M2, M3 antagonist). The M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H3 autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M1 and/or M3 heteroreceptors.

Topics: Animals; Histamine Agonists; Histamine Antagonists; Histamine Release; Hypothalamus, Anterior; Male; Methylhistamines; Muscarinic Agonists; Muscarinic Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Receptors, Muscarinic

The effects of histamine, thioperamide and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) at the noradrenaline release-modulating H3 receptor in the mouse brain were examined. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the inhibitory effect of histamine on the electrically (0.3 Hz) evoked tritium overflow was virtually identical when the time of exposure was 30, 80 or 130 min; after withdrawal of histamine, the evoked overflow recovered within 80 min. The attenuation of the effect of histamine by thioperamide was reversible within 50 min after withdrawal of the antagonist, whereas the attenuation produced by EEDQ remained constant for at least 80 min. In conclusion, the effects of histamine and thioperamide at the H3 receptor are readily reversible, whereas EEDQ appears to be an irreversible antagonist; desensitization of the H3 receptor does not occur.

Topics: Adrenergic alpha-Antagonists; Animals; Brain Chemistry; Cerebral Cortex; Electric Stimulation; Histamine; Histamine Antagonists; Histamine Release; In Vitro Techniques; Male; Mice; Norepinephrine; Piperidines; Quinolines; Receptors, Histamine H3

Histamine, acting via H1 receptors, dose-dependently stimulated [3H]inositol phosphate production in GT1-7 neuronal cells. GT1-7 cells also responded to Substance P but not to other neuroactive drugs tested. Acute histamine pretreatment desensitised the histamine-induced response, resulting in a reduction in the maximal response and a slower time-course of [3H]-inositol phosphate production. The desensitisation phenomenon was reversible, with full recovery by 2 h.

Topics: Animals; Carbachol; Cell Line, Transformed; Dose-Response Relationship, Drug; Glutamic Acid; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Hypothalamus; Inositol Phosphates; Kinetics; Mice; Neurons; Neuropeptide Y; Piperidines; Pyrimidinones; Ranitidine; Receptors, Histamine H1; Serotonin; Substance P; Tritium

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Topics: Anaphylaxis; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mast Cells; Methylhistamines; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Peritoneum; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

The modulation of histamine release by histamine and muscarinic acetylcholine receptors was investigated by using the push-pull technique. The anterior hypothalamic area of the conscious, freely moving rat was superfused through the push-pull cannula with CSF or with CSF containing drugs and the release of endogenous histamine was determined in the superfusate. Hypothalamic superfusion with tetrodotoxin (10 mumol/l) led to a pronounced and sustained decrease in the histamine release rate. Superfusion with compound 48/80 (100 mg/l) was ineffective. Hypothalamic superfusion with the H3 agonist (R)-alpha-methylhistamine inhibited, while superfusion with the H3 antagonist thioperamide enhanced the release of histamine. The release of histamine was inhibited on hypothalamic superfusion with the muscarinic receptor agonists carbachol or oxotremorine. Histamine release was enhanced by atropine, and this release-enhancing effect was abolished by oxotremorine. The selective M1 antagonist pirenzepine (100 mumol/l) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 10 mumol/l), which blocks M1 and M3 receptors, also enhanced the release rate of histamine. On the other hand, 50 and 100 mumol/l methoctramine (M2 receptor antagonist) 10 and 100 mumol/l p-fluoro-hexahydro-siladifenidol (p-F-HHSiD, a M3 receptor antagonist) were ineffective. It is concluded tht histamine released in the hypothalamus originates predominantly from neurons. The release of histamine is modulated by H3 autoreceptors. The histamine release is also modulated by cholinergic neurons which modify histamine release from histaminergic neurons by stimulating M1 muscarinic acetylcholine heteroreceptors probably located on histaminergic neurons.

Topics: Animals; Atropine; Histamine; Histamine Antagonists; Histamine Release; Hypothalamus; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Tetrodotoxin

Bombesin (BN) and its mammalian homologue, gastrin-releasing peptide (GRP), are potent satiety agents and have been implicated in the physiological regulation of food intake. The mechanism(s) of action of this effect remains unclear. There is a functional and anatomic overlap between histamine and BN in relationship to feeding, which led us to hypothesize that BN may mediate its satiety effects through activation of the histaminergic system. To assess this contention, we examined the effects of R-alpha-methylhistamine (alpha-MH) and Imetit, selective H3-receptor agonists that inhibit the release and synthesis of histamine, on BN- or cholecystokinin (CCK)-induced satiety. In this report we present the first evidence for the role of histamine H3 receptors in the mediation of BN-elicited satiety. During the first hour of the 4-h daily feeding session, BN reduced food intake by > 50% relative to the control condition; this suppression was blocked by prior treatment with the H3-receptor agonist, alpha-MH. This blockade of BN-induced satiety was dose related and selective to BN as alpha-MH failed to attenuate sulfated CCK-8-induced satiety. When alpha-MH was administered alone, it failed to significantly affect food intake. The specificity of this effect was further supported by the demonstration that another H3 agonist, Imetit, was also able to block the feeding-suppressant effects of BN. Furthermore, thioperamide, an H3-receptor antagonist, blocked these effects of Imetit.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Bombesin; Eating; Gastrin-Releasing Peptide; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Methylhistamines; Motor Activity; Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Satiation; Sincalide; Thiourea

1. The effect of (R)-alpha-methylhistamine (R-alpha-mHA), a selective histamine H3-receptor agonist, on increases in blood pressure and heart rate mediated by activation of the sympathetic nervous system induced by electrical stimulation of the spinal cord, was characterized in the vagotomized, pithed guinea-pig. 2. The frequency-dependent nature of (R)-alpha-mHA's effect on sympathetic cardiopressor responses was studied at frequencies between 1 and 20 Hz. (R)-alpha-mHA (10-100 micrograms kg-1, i.v.) produced a dose-dependent inhibition of the stimulated increase in both blood pressure (BP) and heart rate (HR). The inhibition was inversely related to frequency and maximum inhibition (BP, 61% at 1 Hz; HR, 50% at 1 Hz) was seen with 100 micrograms kg-1 of (R)-alpha-mHA. Treatment with the H3 receptor inactive stereoisomer, (S)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not inhibit the neurogenic sympathetic cardiopressor responses. 3. Pretreatment with thioperamide (1 mg kg-1, i.v.), a histamine H3 receptor antagonist, blocked (R)-alpha-mHA's inhibitory effect on stimulation-induced sympathetic cardiopressor responses. 4. Combined pretreatment with the H2-receptor antagonist cimetidine (3 mg kg-1, i.v.) and the H1-receptor antagonist chlorpheniramine (0.3 mg kg-1, i.v.) did not attenuate (R)-alpha-mHA's inhibitory effects. 5. (R)-alpha-mHA (100 micrograms kg-1) had no effect on the hypertensive or tachycardia effects induced by adrenaline (1 and 3 micrograms kg-1, i.v.). 6. Treatment with a combination of prazosin (1 mg kg-1, i.v.) and yohimbine (1.5 mg kg-1, i.v.) to block alpha 1- and alpha 2-adrenoceptors, abolished the sympathetic hypertension without affecting the inhibition of sympathetic tachycardia induced by (R)-alpha-mHA. Conversely, pretreatment with the beta-adrenoceptor antagonist propranolol (1 mg kg-1, i.v.), which blocked the sympathetic tachycardia, did not block (R)-alpha-mHA's inhibition of sympathetic hypertensive responses. 7. In adrenalectomized guinea-pigs, (R)-alpha-mHA (100 micrograms kg-1, i.v.) also produced a frequency-dependent inhibition of sympathetic hypertensive cardiopressor responses that was not significantly different from intact animals. 8. These results demonstrate that (R)-alpha-mHA produces a frequency-dependent inhibition of the cardiopressor responses due to activation of the sympathetic innervation to the resistance vessels and the heart.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adrenalectomy; Animals; Blood Pressure; Chlorpheniramine; Cimetidine; Drug Interactions; Electric Stimulation; Epinephrine; Guinea Pigs; Heart; Heart Rate; Histamine Agonists; Male; Methylhistamines; Piperidines; Prazosin; Spinal Cord; Sympathetic Nervous System; Vagotomy; Yohimbine

The effects of thioperamide, an H3 antagonist, and histamine H1 and H2 antagonists (s.c.) on morphine (s.c. or i.c.v.)- and U-50,488H (i.c.v.)-induced antinociception in male ddY mice were examined using the hot-plate (55 degrees C) test. Thioperamide significantly inhibited morphine-induced antinociception, but not U-50,488H-induced antinociception. The suppressive effect of thioperamide on morphine-induced antinociception was reversed by the H1 antagonist pyrilamine, but not by the H2 antagonist zolantidine. On the other hand, pyrilamine significantly potentiated the antinociception induced by morphine, but not that induced by U-50,488H. Zolantidine significantly inhibited morphine-induced antinociception in a dose-dependent manner, but not U-50,488H-induced antinociception. Both astemizole, an H1 antagonist, and ranitidine, an H2 antagonist, which are known to barely cross the blood brain barrier, did not affect morphine-induced antinociception. These results suggest that morphine-induced antinociception may be potentiated by activation of H2 receptors and suppressed by activation of H1 receptors in the brain. Furthermore, neuronal histamine release induced by thioperamide may suppress morphine-induced antinociception through H1 receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Drug Interactions; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Mice; Mice, Inbred Strains; Morphine; Neurons; Nociceptors; Piperidines; Pyrrolidines

1. We determined the affinities of ten novel H3 receptor antagonists in an H3 receptor binding assay and their potencies in two functional H3 receptor models. The novel compounds differ from histamine in that the aminoethyl side chain is replaced by a propyl or butyl chain linked to a polar group (amide, thioamide, ester, guanidine, guanidine ester or urea) which, in turn, is connected to a hexocyclic ring or to an alicyclic ring-containing alkyl residue [corrected]. 2. The specific binding of [3H]-N alpha-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the ten compounds at pKi values ranging from 7.56 to 8.68. 3. Inhibition by histamine of the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]-noradrenaline was antagonized by the ten compounds and the concentration-response curve was shifted to the right with apparent pA2 values ranging from 7.07 to 9.20. 4. The electrically induced contraction in guinea-pig ileum strips (which was abolished by atropine) was inhibited by the H3 receptor agonists R-(-)-alpha-methylhistamine (pEC50 7.76), N alpha-methylhistamine (7.90) and imetit (8.18). The concentration-response curve of R-(-)-alpha-methylhistamine was shifted to the right by thioperamide (apparent pA2 8.79) and by the ten novel compounds (range of pA2 values 6.64-8.81). 5. The affinities and potencies were compared by linear regression analysis. This analysis was extended to thioperamide, the standard H3 receptor antagonist, which is also capable of differentiating between H3A and H3B sites. Comparison of the apparent pA2 values in the two functional H3 receptor models yielded a regression coefficient of 0.77 (P<0.02). When the pA2 of the drugs in the mouse brain cortex were compared to the pXj for H3 sites (ten novel compounds) and for H3A sites (thioperamide), a significant correlation (r = 0.87; P<0.001) was obtained. There was, however, no significant correlation when the pKi of thioperamide for H3B sites was used instead (r = 0.52). In a similar manner, comparison of the pA2 in the guinea-pig ileum with the pKi in the binding assay yielded a significant correlation(r = 0.70, P <0.05) only when the pKi of thioperamide for H3A sites was used but not when its pKi forH3B sites was considered (r = 0.17, NS).6 On the basis of these results, structure-activity relationships for the novel H3 receptor antagonists,and the nature of the H3 receptors in the guinea-pig ileum and mouse

Topics: Animals; Binding Sites; Cerebral Cortex; Female; Guinea Pigs; Histamine Antagonists; Ileum; In Vitro Techniques; Male; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Structure-Activity Relationship

The effects of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine and antagonist thioperamide on stimulant-induced locomotor activity in the mouse were examined. Amphetamine (1 mg.kg-1 s.c.), apomorphine (2 mg.kg-1 s.c.) or cocaine (5 mg.kg-1 s.c.) increased locomotor activity. Neither thioperamide (10 mg.kg-1 i.p.) nor (R)-alpha-methylhistamine (20 mg.kg-1 i.p.) affected spontaneous locomotor activity in their own right. (R)-alpha-Methylhistamine (0.3, 3 or 20 mg.kg-1 i.p.) also had no effect on amphetamine (1 mg.kg-1 s.c.)-induced locomotor activity. In contrast, thioperamide (0.2-10 mg.kg-1 i.p. or 0.3-20 micrograms i.c.v.) inhibited, in a dose-dependent manner, the hyperactivity response induced by amphetamine (1 mg.kg-1 s.c.). (R)-alpha-Methylhistamine (20 mg.kg-1 i.p.) completely reversed the inhibitory response to thioperamide (2 mg.kg-1 i.p.). Thioperamide (2 or 10 mg.kg-1 i.p.) also inhibited apomorphine (2 mg.kg-1 s.c.)- and, to a lesser extent, cocaine (5 mg.kg-1 s.c.)-induced hyperactivity. We therefore conclude that antagonism of the central histamine H3 receptor inhibits, to a varying degree, the effects of locomotor stimulants.

Topics: Amphetamine; Animals; Apomorphine; Central Nervous System Stimulants; Cocaine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Motor Activity; Piperidines

Potential species differences in cardiovascular responses to histamine H3 receptor activation were studied in the conscious guinea pig, rabbit, normotensive rat and the spontaneously hypertensive rat. R-alpha-Methylhistamine (100 micrograms/kg i.v.) decreased blood pressure in both the guinea pig and the rabbit. In the guinea pig, R-alpha-methylhistamine decreased heart rate, whereas in the rabbit it produced a tachycardia. In the normotensive rat and spontaneously hypertensive rat, R-alpha-methylhistamine (100 micrograms/kg i.v.) had no effect on blood pressure and heart rate. The cardiovascular action of R-alpha-methylhistamine in the guinea pig and rabbit was blocked by pretreatment with thioperamide (1.0 mg/kg i.v.) but not by chlorpheniramine (0.3 mg/kg i.v.) or cimetidine (3.0 mg/kg i.v.), respectively. These results indicate species differences in cardiovascular responses to histamine H3 receptor activation.

Topics: Animals; Blood Pressure; Cimetidine; Guinea Pigs; Heart Rate; Hemodynamics; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Piperidines; Rabbits; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Histamine H3; Species Specificity

To investigate whether histamine receptor ligands influence the in vivo-release of acetylcholine in the ventral striatum, this brain region was superfused with histamine receptor agonists or antagonists through a push-pull cannula and drug effects on the release of acetylcholine were investigated. Histamine, the H1 receptor agonist 2-thiazolyl-ethylamine and the H3 receptor antagonist thioperamide enhanced acetylcholine release, while the H3 receptor agonist (R)-alpha-methylhistamine was ineffective. The results indicate that H1 receptors and H3 receptors modulate acetylcholine release. The thioperamide-induced increase of acetylcholine release might be exerted via H3-receptors located on cholinergic terminals. Alternatively, thioperamide might enhance acetylcholine release by increasing endogenous histamine release via H3 autoreceptors. It is concluded that, via stimulation of striatal H1- and H3 receptors, histaminergic neurons are involved in the regulation of cholinergic neuronal activity in the ventral striatum.

Topics: Acetylcholine; Animals; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Neostriatum; Piperidines; Rats; Receptors, Histamine

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine

Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.

Topics: Cerebral Cortex; Cimetidine; Evoked Potentials; Histamine; Histamine Antagonists; Humans; Hypnotics and Sedatives; Membrane Potentials; Neurons; Piperidines; Potassium Channels; Pyrilamine; Receptors, Histamine H1

The action of (R)-alpha-methylhistamine (alpha-MeHA), a selective H3-receptor agonist, on field stimulation induced contraction of guinea pig vas deferens was composed of 2 components: the "inhibition" (0.1-100 nmon.L-1) and the "enhancement" (1-10 mumol.L-1). In the presence of histamine H1 antagonist, chlorpheniramine (1 mumol.L-1), alpha-MeHA (0.1 nmol.L-1-10 mumol.L-1) showed only a concentration-dependent inhibition. Selective histamine H3-receptor antagonist, thioperamide (1 nmol.L-1-10 mumol.L-1) antagonized the inhibitory effect of alpha-MeHA and increased the contractile amplitude of vas deferens elicited by field pulses when thioperamide was used alone. alpha-MeHA 10 mumol.L-1 enhanced the contractile amplitude, which was reversed by chlorpheniramine 1 mumol.L-1, but not by ranitidine (1 mumol.L-1). Pyridelethylamine, an H1-receptor agonist, facilitated concentration-dependently the contractile response of vas deferens. The effect was antagonized by chlorpheniramine, but not by ranitidine. Dimaprit, an H2-receptor agonist had no effect on the field stimulation induced sympathetic response. Both alpha-MeHA and pyridelethylamine failed to influence the contraction of vas deferens elicited by direct field stimulation in smooth muscle or by exogenously applied norepinephrine. It was concluded that histamine H1- and H3-receptors existed in sympathetic terminals of guinea pig vas deferens and facilitated or inhibited the sympathetic neurotransmission.

Topics: Animals; Chlorpheniramine; Dimaprit; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Ranitidine; Sympathetic Nervous System; Synaptic Transmission; Vas Deferens

Histamine H3 antagonists have been reported to discriminate subclasses of histamine H3 agonist binding in rat cortical membranes. This phenomenon was investigated by autoradiography of cryostat sections of rat forebrain labelled with [3H]N alpha-methylhistamine ([3H]NAMH, 4 nM). Displacement curves with thioperamide detected a single site in cortex and striatum (pIC50 = 8.18 +/- 0.03). However, Hill coefficients (nH = 0.51 +/- 0.12) suggested the possible presence of multiple binding sites. Displacement with burimamide was consistent with two site models in all brain regions examined (pIC50(A) = 7.9 +/- 1.5; pIC50(B) = 5.6 +/- 0.7), except for the medial septum where a single site was detected. Elsewhere, the relative abundance of the two sites displaced by burimamide (H3A:H3B) appeared to be 1:2. Thioperamide may have failed to discriminate two sites because the IC50s were too similar to be distinguished in the present autoradiographic study.

Topics: Animals; Autoradiography; Binding Sites; Binding, Competitive; Brain; Burimamide; Cerebral Cortex; Corpus Striatum; Histamine Antagonists; Male; Methylhistamines; Organ Specificity; Piperidines; Prosencephalon; Rats; Rats, Wistar; Receptors, Histamine H3; Tritium

An HPLC method using an ovomucoid-conjugated column has been developed for measurement of thioperamide, a histamine H3 antagonist, with a minimum quantitation limit of 0.05 micrograms mL-1. The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg-1), the plasma concentration decreased monoexponentially with a half-life of 26.9 min. The apparent total body clearance of thioperamide from rat plasma was 74.6 mL min-1 kg-1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.

Topics: Animals; Chromatography, High Pressure Liquid; Half-Life; Histamine Antagonists; Injections, Intravenous; Male; Models, Biological; Ovomucin; Piperidines; Rats; Rats, Wistar; Tissue Distribution

1. Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2. A wide range of i.c.v. doses of histamine 2HCl was studied. Relatively high dose were dose-dependently antinociceptive in all three tests: 5-100 micrograms per rat in the paw pressure test, 5-50 micrograms per mouse in the abdominal constriction test and 50-100 micrograms per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 microgram per rat in the paw pressure test and 0.1-1 microgram per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3. The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40 mg kg-1) and i.c.v. (1.1-10 micrograms per rat and 3.4-10 micrograms per mouse) routes. 4. The histamine H3 agonist, (R)-alpha-methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 microgram per rat and 3 microgram per mouse, or i.p. administration of 100 mg kg-1 in mice. In rats 20 mg kg-1, i.p. elicited hyperalgesia only 4 h after treatment. 5. Thioperamide-induced antinociception was completely prevented by pretreatment with a non-hyperalgesic i.p. dose of (R)-alpha-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6. L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500 mg kg-1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg-1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg-1, i.p. showed their maximum effect 2 h after treatment. 7. The histamine N-methyltransferase inhibitor, metoprine, elicited a long-lasting, dose-dependent antinociception in all three tests by both i.p. (10-30 mg kg-1) and i.c.v. (50-100 micrograms per rat) routes. 8. To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-alpha-fluoromethylhistidine and

Topics: Analgesics; Animals; Histamine; Histidine; Hyperalgesia; Male; Methylhistamines; Methylhistidines; Mice; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Sensory Thresholds

Starting from the structure of thioperamide, a known H3-antagonist, a new series of compounds with a benzothiazole nucleus instead of the cyclohexylcarbothioamide moiety was synthesized. Various substituents, selected by experimental design, were introduced in position 6 of the benzothiazole nucleus, in order to change its physico-chemical characteristics. The lipophilicity of the synthesized compounds was measured by means of RP-HPLC, and their H3-receptor affinity was evaluated by competitive binding assays on rat cortex synaptosomes, with the labelled ligand N alpha-[3H]methylhistamine. A QSAR analysis was performed on the experimental data, using also substituent constants taken from the literature. The newly synthesized compounds showed lower H3-affinities than thioperamide; quantitative structure-activity relationships, described by models obtained with PLS and MRA techniques, were observed among benzothiazole derivatives. According to these relationships, any attempt to improve the potency of these compounds should involve the substitution of the benzothiazole moiety with less bulky and/or more flexible structures, which should also be less lipophilic and allow better electronic interactions with the binding site. 1-(Benzothiazol-2-yl)-4-[(1H)-imidazol-4-yl]piperidine represents a limit structure for H3-activity, since it seems impossible to improve its affinity by means of substitution in the studied position of the benzothiazole nucleus, as shown by predictions performed by a PLS model.

Topics: Animals; Binding, Competitive; Cerebral Cortex; Crystallization; Histamine Antagonists; In Vitro Techniques; Ligands; Piperidines; Rats; Receptors, Histamine H3; Regression Analysis; Solubility; Structure-Activity Relationship; Synaptosomes

The influence of N-ethylmaleimide (NEM) on sympathetic neurotransmission induced by field stimulation on the isolated guinea pig vas deferens was studied. Application of (R)-alpha-methylhistamine (0.1 mcmol/l) significantly inhibited the sympathetic response by 26.0%, while thioperamide facilitated the sympathetic contraction of vas deferens evoked by field pulses by 221.1%. Pretreatment of vas deferens with NEM (60 mcmol/l) for 15 min abolished both the inhibitory and facilitatory effects. Attenuation of thioperamide facilitatory effect by NEM was not significantly altered when the H3-receptors were occupied by thioperamide prior to and during NEM treatment. The results suggest that effects mediated by H3-receptors in the guinea pig vas deferens were NEM-sensitive and possibly transmitted by Gi or Go proteins.

Topics: Animals; Electric Stimulation; Ethylmaleimide; GTP-Binding Proteins; Guinea Pigs; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Receptors, Histamine H3; Receptors, Presynaptic; Signal Transduction; Sympathetic Nervous System; Synaptic Transmission; Vas Deferens

Experiments were undertaken to determine the effect of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine on the amplitude of neurally evoked electrodermal (sudomotor) responses in anesthetized cats. (R)-alpha-Methylhistamine produced comparable dose-related depressions of these evoked sympathetic-cholinergic electrodermal responses elicited by either pre- or postganglionic nerve stimulation. Responses evoked by i.a. methacholine were not depressed by pretreatment with (R)-alpha-methylhistamine. (R)-alpha-Methylhistamine inhibition of preganglionic evoked responses was antagonized by pretreatment with the histamine H3 receptor antagonist thioperamide, but not by pretreatment with selective blockers of histamine H1 or histamine H2 receptors (chlorpheniramine or cimetidine). Pretreatment with thioperamide did not antagonize presynaptic inhibition produced by i.v. (-)-epinephrine, nor did rauwolscine block the inhibition produced by (R)-alpha-methylhistamine. These results suggest that (R)-alpha-methylhistamine stimulates presynaptic histamine H3 receptors located on sudomotor postganglionic nerve endings to depress neurally evoked release of acetylcholine. (R)-alpha-Methylhistamine does not appear to act at an autonomic ganglionic site in this system.

Topics: Animals; Cats; Chlorpheniramine; Cimetidine; Electric Stimulation; Female; Histamine Agonists; Male; Methacholine Chloride; Methylhistamines; Parasympathetic Nervous System; Piperidines; Receptors, Histamine H3; Skin; Sympathetic Nervous System

Histamine plays an important role in the control of gastric acid secretion by activating H2 receptors located on parietal cells. In gastric mucosa, histamine is stored both in mast cells and in enterochromaffin-like cells, especially in rodents. It has been proposed that histamine may regulate its own synthesis and/or release through receptors pharmacologically distinct from H1- and H2-receptor subtypes. In this article, we studied the regulation by histamine of histidine decarboxylase (HDC) activity (enzyme responsible for the formation of histamine by decarboxylation of L-histidine) in a fraction of isolated rabbit gastric mucosal cells enriched in mucous and endocrine cells. Histamine and (R)-alpha-methylhistamine (H3 receptor agonist) dose dependently inhibited HDC activity with the same potency (mean effective concn: 32.2 +/- 0.7 and 50.5 +/- 3.1 pM, respectively) and efficacy (35 and 36% inhibition, respectively). In contrast, the H2 agonist dimaprit was devoid of effect. The H3 antagonist thioperamide was found to decrease the histamine- or (R)-alpha-methylhistamine-induced inhibition of HDC activity (mean ineffective concn = 28.3 +/- 1.8 and 9.87 +/- 0.8 nM, respectively), whereas H1 (promethazine) and H2 (ranitidine) antagonists were unable to affect HDC activity. Moreover, high concentrations of thioperamide (1-10 microns) increased histamine release from these cells. All these results allowed us to conclude that, in gastric mucosa, histamine downregulates its own synthesis (and perhaps release) through the stimulation of autoreceptors with pharmacological characteristics of H3 receptors. However, the relationship between histamine synthesis and release remains unclear and needs further investigation.

Topics: Animals; Dose-Response Relationship, Drug; Gastric Fundus; Gastric Mucosa; Histamine; Histamine Antagonists; Histamine Release; Histidine Decarboxylase; Homeostasis; In Vitro Techniques; Piperidines; Promethazine; Rabbits; Ranitidine; Receptors, Histamine H3

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Topics: Anaphylaxis; Animals; Anticonvulsants; Betahistine; Cimetidine; Dimaprit; Histamine H2 Antagonists; Histamine Release; In Vitro Techniques; Indicators and Reagents; Male; Mast Cells; Piperidines; Pyrilamine; Rats; Rats, Wistar

1. The effect of the selective histamine H3 receptor agonist, R-alpha-methylhistamine given intravenously (10-100 micrograms kg-1) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea-pigs. 2. R-alpha-methylhistamine produced a dose-dependent hypotension and fall in TPR at 30 and 100 micrograms kg-1. A decrease in heart rate (HR) was observed at a dose of 100 micrograms kg-1. R-alpha-methylhistamine (10-100 micrograms kg-1) also produced a dose-dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. 3. Histamine H1 and H2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg-1) and cimetidine (3.0 mg kg-1) did not alter the haemodynamic actions of R-alpha-methyl-histamine (100 micrograms kg-1, i.v.). Pretreatment with the selective H3 antagonist, thioperamide (1 mg kg-1), completely blocked the action of R-alpha-methylhistamine on haemodynamic parameters. 4. To study the mechanism of action of R-alpha-methylhistamine, the vasodilator hydralazine (1 mg kg-1, i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea-pigs pretreated with ipratropium (50 micrograms kg-1, i.v.). Hydralazine had no effect on HR, SV or CO. 5. R-alpha-methylhistamine (100 micrograms kg-1) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 micrograms kg-1). On the other hand, the vasodilator hydralazine (1 mg kg-1, i.v.) inhibited the effects of adrenaline (3 micrograms kg-1) on TPR and RPP. The effect of both doses of adrenaline on BP were attenuated by hydralazine. Therefore, the inhibitory effects of R-alpha-methylhistamine are not mediated through a direct action on vascular smooth muscle.6. In adrenalectomized guinea-pigs, R-alpha-methylhistamine (100 microg kg-1) produced a drop in BP and HR.There was no difference between the effects of R-alpha-methylhistamine on blood pressure and heart rate in adrenalectomized and non-adrenalectomized guinea-pigs.7. These results show that activation of peripheral H3 receptors lowers basal BP, HR and TPR, most likely by a peripheral prejunctional mechanism. The fall in BP and TPR is probably due to a decrease in noradrenaline release from sympathetic effector nerves innervating the resistance blood vessels.

Topics: Adrenalectomy; Anesthesia; Animals; Cardiac Output; Dose-Response Relationship, Drug; Guinea Pigs; Hemodynamics; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Hydralazine; Male; Methylhistamines; Muscle, Smooth, Vascular; Piperidines; Receptors, Histamine H3; Vascular Resistance

The pharmacological activity of the histamine H3 receptor antagonist VUF 9153 (S-[3-(4(5)-imidazolyl)]propyl-N-(4-chlorobenzyl)isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [3H]N alpha-methylhistamine binding to rat cortex/hippocampal membranes (pKi = 9.77 +/- 0.03) and antagonised the inhibitory responses to (R)-alpha-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pKB = 9.95 +/- 0.07). In these assays, VUF 9153 was 10-50-fold more potent than the prototype H3 receptor antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H1 or H2 receptors. Systemic administration of VUF 9153 (s.c. or p.o.) dose-dependently inhibited the ex vivo binding of [3H]N alpha-methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-alpha-methylhistamine. Calculation of ED50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered s.c. or p.o., was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective antagonist for histamine H3 receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H3 receptors and can inhibit H3 receptor-mediated functional responses in vivo.

Topics: Animals; Cerebral Cortex; Dose-Response Relationship, Drug; Drinking; Electric Stimulation; Guinea Pigs; Hippocampus; Histamine Agonists; Histamine Antagonists; Ileum; Imidazoles; In Vitro Techniques; Male; Methylhistamines; Muscle, Smooth; Piperidines; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Thiourea

The recent availability of potent and selective ligands, namely R-(alpha)-methylhistamine and thioperamide, led to conclusive progresses as regards histamine H3-receptor knowledge. The aim of this work is to investigate by in vitro tests the pharmacological properties of new amino and methyl derivatives of the H3-antagonist thioperamide. Such original compounds, developed by the modulation of the thioperamide imidazolyl moiety, were assayed at guinea-pig ileal contractile H1-, atrial chronotropic H2- and enteric neuronal H3-receptors. None of the drugs exhibited interaction with H1 or H2 sites. On electrically stimulated ileum, two of the thioperamide methyl derivatives competitively antagonized the inhibitory effect of the H3-agonist R-(alpha)-methylhistamine. On the basis of the Schild analysis, the more active isomer (compound IV) displayed an affinity at H3-receptors only five times lower than thioperamide. These results could contribute to elucidate further the structural features required to develop potent and selective H3-antagonists. On the other hand, to prove the hypothesized apparent heterogeneity between peripheral and central H3-sites, as emerged by pharmacological and binding studies, autoradiographic investigations are in progress.

Topics: Animals; Electric Stimulation; Female; Guinea Pigs; Heart Atria; Heart Rate; Histamine; Ileum; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

We investigated the effects of thioperamide, a histamine H3-receptor antagonist, in a light/dark test measuring anxiety in mice. Thioperamide (20 mg/kg) slightly affected the locomotion and time spent in a light zone, and shuttle crossing. However, the decreases of these parameters were significant only when the animals were pretreated with zolantidine, a histamine H2-receptor antagonist. Moreover, the decreased parameters induced by the combination of thioperamide and zolantidine were reversed by pretreatment with pyrilamine, a histamine H1-receptor antagonist. These data suggest that thioperamide induces the release of neuronal histamine, which in turn stimulates both H1- and H2-receptors to produce the anxiogenic effect. The stimulation of histamine H1-receptors may mediate the anxiety, while H2-receptors may play a role in masking the anxiogenic effect. Thus, the present study suggests the involvement of endogenous neuronal brain histamine in anxiety. In the biochemical study, a previous report showed that thioperamide accelerated the release of neuronal histamine in the brains of mice [Sakai et al., Life Sciences, 48, 2397-2404(1991)]. This study also demonstrated that thioperamide did not affect the turnover rate of noradrenaline, dopamine, or serotonin in the brains of mice, which indicates that thioperamide is a good pharmacological tool for accelerating the release of neuronal histamine in the brain.

Topics: Animals; Anxiety; Behavior, Animal; Brain; Darkness; Disease Models, Animal; Dopamine; Histamine Antagonists; Light; Male; Mice; Mice, Inbred ICR; Motor Activity; Norepinephrine; Piperidines; Serotonin

Frequency-dependent pupillary dilations were evoked by electrical stimulation of the pre- or post-ganglionic cervical sympathetic nerve (sympatho-excitation) or the hypothalamus (parasympatho-inhibition) in sympathectomized anesthetized cats. Systemic administration of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine (R alpha MeHA) produced a dose-dependent depression of mydriasis due to direct neural sympathetic activation but had no effect on responses elicited by parasympathetic withdrawal. The histamine H2 receptor agonist, dimaprit, was inactive. R alpha MeHA was much more effective in depressing sympathetic responses obtained at lower frequencies when compared to higher frequencies of stimulation. Responses evoked both pre- and postganglionically were inhibited by R alpha MeHA. This peripheral sympatho-inhibitory action of R alpha MeHA was antagonized by the histamine H3 receptor blocker thioperamide but not by intravenous pretreatment with the histamine H1 receptor antagonist chlorpheniramine. Histamine H2 receptor blockers cimetidine and ranitidine were also without effect. R alpha MeHA did not depress pupillary responses elicited by i.v. (-)-adrenaline. The results demonstrate that histamine H3 receptors modulate sympathetic activation of the iris at a site proximal to the iris dilator muscle. The predominant mechanism of action appears to the prejunctional inhibition of noradrenaline release from postganglionic sympathetic nerve endings. However, a concomitant ganglionic inhibitory action cannot be excluded.

Topics: Animals; Cats; Dose-Response Relationship, Drug; Electric Stimulation; Female; Histamine Agonists; Histamine Antagonists; Iris; Male; Methylhistamines; Neuromuscular Junction; Piperidines; Pupil; Receptors, Histamine H3; Receptors, Presynaptic; Sympathetic Nervous System

Using probes to manipulate hypothalamic neuronal histamine, we report here that changes in neuronal histamine modulate physiological feeding behavior in rats. Infusion of alpha-fluoromethylhistidine (FMH), a "suicide" inhibitor of histidine decarboxylase (HDC), into the third cerebroventricle induced feeding in the early light phase when the histamine synthesis was most accelerated. FMH at an optimum 2.24 mumol dose elicited feeding in 100% of rats. Treatment of FMH specifically and selectively decreased concentration of histamine without affecting concentrations of catecholamines in the hypothalamus. Immediately before the dark phase, when the histamine synthesis was normally lower, FMH infusion did not affect feeding-related parameters such as meal size, meal duration or latency to eat. Conversely, thioperamide, which facilitates both synthesis and release of neuronal histamine by blocking presynaptic autoinhibitory H3 receptors, significantly decreased food intake after infusion of a 100-nmol dose into the third cerebroventricle. The effect of thioperamide was abolished with i.p. injection of 26 mumol/kg chlorpheniramine, an H1antagonist. FMH at 224 nmol was microinfused bilaterally into the feeding-related nuclei in the hypothalamus. The ventromedial nucleus (VMH) and the paraventricular nucleus (PVN), but not the lateral hypothalamus, the dorsomedial hypothalamus or the preoptic anterior hypothalamus were identified as the active sites for the modulation. Neuronal histamine may convey suppressive signals of food intake through H1 receptors in the VMH and the PVN with diurnal fluctuation.

Topics: Animals; Binding Sites; Catecholamines; Cerebral Ventricles; Eating; Feedback; Histamine; Histamine Antagonists; Histidine Decarboxylase; Hypothalamus; Infusions, Parenteral; Male; Methylhistidines; Neurons; Piperidines; Rats; Rats, Wistar

1. Histamine stimulated the accumulation of total [3H]-inositol phosphates (IPn) in control HeLa cells with an EC50 of 3.7 +/- 0.7 microM in the presence of 10 mM LiCl. The maximum response to histamine after 15 min incubation was 43 +/- 5% over basal accumulation and occurred at a concentration of 1 mM histamine. 2. The histamine-induced IPn production in HeLa cells was confirmed as H1 receptor-mediated, since the H1 antagonist mepyramine (10(-6) M) inhibited the histamine response (10(-4) M) by 83 +/- 7%, whereas the H2 antagonist, ranitidine (10(-4) M), and H3 antagonist, thioperamide (10(-6) M), were ineffective. 3. Histamine (10(-4) M) pretreatment of HeLa cells for 30 min desensitized the subsequent histamine-induced IPn accumulation. The desensitized cells accumulated IPn in response to histamine with an EC50 of 1.7 +/- 0.7 microM after 15 min incubation. The maximum histamine-induced IPn accumulation at 10(-4) M was 19 +/- 5% over basal and was significantly lower (P < 0.03) than the maximum response in control cells. 4. The desensitization of histamine-induced IPn accumulation was time-dependent and, at a desensitizing histamine concentration of 10(-4) M, the half-maximal attenuation occurred after approximately 9 min and maximum desensitization was achieved by 15-20 min. The desensitization of the IPn accumulation was a reversible phenomenon and full recovery of the response occurred 150 min after the removal of the desensitizing histamine-containing medium. The half-time for the recovery of the histamine-induced response was estimated at 120 min. 5. Bradykinin stimulated IPn, accumulation in HeLa cells, and the ECm in control cells of 1.9 +/- 0.2 nM was not significantly different from the EC50 value from histamine-pretreated cells of 1.6 +/- 0.9 nM. The bradykinin response at 1 microM was 194 +/- 48% over basal IPn accumulation in control cells and this value was significantly different (P <0.04) from the 1 microM bradykinin-induced IPn accumulation in histamine pretreated HeLa cells of 143 +/- 38% over basal.6. NaF stimulated IP,, accumulation in control HeLa cells in a dose-related manner, with the maximum effect occurring at 15-20 mM. The EC50 value for NaF-stimulated IPn accumulation in control cells was 10.5 +/- 1.1 mm and the maximum response was 136 +/- 41% over basal after 20 min incubation. In histamine desensitized HeLa cells the EC50 value for NaF was 12.3 +/- 0.4 mM after 20 min stimulation,which was not significantly different fro

Topics: Bradykinin; HeLa Cells; Histamine; Humans; Inositol; Inositol Phosphates; Piperidines; Pyrilamine; Ranitidine; Receptors, Histamine H1; Sodium Fluoride

Effects of intracerebroventricular (i.c.v) injection of histamine (Hi) and its related compounds on prolongation of the response latency ensuing after a long interruption of learning were studied by testing the active avoidance response in old rats. After Hi application at doses of 50 and 100 ng, the response latency became significantly shorter than that determined in the pre-injection periods, suggesting that Hi facilitates memory retrieval in old rats. H1-agonists, 2-methylHi and 2-thiazolylethylamine, effected a dose-related shortening of response latency as seen after Hi application, whereas H2-agonists, 4-methylHi and impromidine, failed to prompt the response latency. Simultaneous i.c.v. injection of pyrilamine, a H1-antagonist and Hi abolished the Hi-induced shortening of response latency. Furthermore, intraperitoneal administration of histidine at doses of 200 and 500 mg/kg significantly shortened the response latency. Neither (R)-alpha-methylHi nor thioperamide caused a significant effect indicating that H3-receptor may not be involved in Hi-induced facilitation of memory retrieval. Based on these findings, it may be concluded that Hi takes an active part in facilitating memory recall via H1-receptor in old rats.

Topics: Acetylcholine; Aging; Animals; Anticonvulsants; Avoidance Learning; Cerebrovascular Circulation; Cimetidine; Dose-Response Relationship, Drug; Exploratory Behavior; Histamine; Histamine Agonists; Injections, Intraventricular; Male; Memory; Methylhistamines; Motor Activity; Piperidines; Pyrilamine; Rats; Rats, Wistar

Histamine (HA) stimulates prolactin secretion via H1 and H2 receptors. In the present study, we examined the role of a third subtype of receptor recently described in brain, the H3-HA receptor, on prolactin secretion in male rats. R(-)alpha-methyl-HA (alpha-MHA), a selective H3 receptor agonist, was injected into the lateral ventricle of the brain in freely moving rats. alpha-MHA produced a dose-dependent (1-5 micrograms) and long-lasting increase in plasma prolactin levels. This increase was observed from 15 to 60 min after injection of alpha-MHA. Its stimulatory action was prevented by thioperamide (20 micrograms i.v.t), a selective H3 antagonist. This compound, injected intraventricularly, lacked effect by itself on basal plasma prolactin levels. Neither pyrilamine (H1 antagonist; 60 micrograms i.v.t.) nor ranitidine (H2 antagonist; 60 micrograms i.v.t.) affected alpha-MHA-induced prolactin release. The stimulatory effect was still present when brain HA was depleted by alpha-fluoromethylhistidine (30 mg/kg i.p.). Our findings suggest that alpha-MHA evokes prolactin release by activation of postsynaptic H3 receptors.

Topics: Animals; Brain; Injections, Intraventricular; Kinetics; Male; Methylhistamines; Methylhistidines; Piperidines; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Histamine

The effect of (R)alpha-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H3 receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H3 receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mumol/kg/h caused a significant reduction of the 2-deoxy-D-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mumol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mumol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mumol/kg/h) produced a significant increase both in acid output and in plasma gastrin. These results suggest that activation of H3 receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H3 receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.

Topics: Animals; Deoxyglucose; Dogs; Female; Gastric Acid; Gastric Fistula; Gastrins; Male; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effect of the selective H3 receptor agonist (R)-alpha-methylhistamine and antagonist thioperamide on water consumption in the rat were examined. (R)-alpha-Methylhistamine (0.1-20 mg.kg-1 i.p.) evoked a dose-dependent increase in water consumption the maximum effect being 310 +/- 23% (n = 67) above the vehicle control response. Thioperamide (0.2,2 and 10 mg.kg-1 i.p.) alone had no effect on water consumption. However, the stimulatory effect of (R)-alpha-methylhistamine on water consumption was antagonised by thioperamide in a dose-dependent manner, whereas the H1 receptor antagonist mepyramine and the H2 receptor antagonist loxtidine were without effect. It is therefore concluded that the H3 receptor may play a role in the regulation of water consumption in the rat.

Topics: Animals; Drinking; Histamine; Histamine Antagonists; Male; Methylhistamines; Nicotinic Acids; Piperidines; Pyrilamine; Rats; Receptors, Histamine; Receptors, Histamine H3; Tetrazoles; Triazoles

The effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Thioperamide significantly and dose dependently decreased the duration of each phase of convulsion and raised the electroconvulsive threshold. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine, a histamine H3 receptor agonist. These findings suggest that the effect of thioperamide on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, an effect mediated by histamine H3 receptors. The anticonvulsant effect of thioperamide was antagonized strongly by mepyramine (or pyrilamine), a centrally acting histamine H1 receptor antagonist, but not by zolantidine, a centrally acting histamine H2 receptor antagonist. Thus, the blockade by mepyramine of the thioperamide-induced decrease in seizure susceptibility indicates that histamine released by thioperamide from the histaminergic nerve terminals interacts with the histamine H1 receptors of postsynaptic neurons. These findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures.

Topics: Animals; Anticonvulsants; Electroshock; Histamine Antagonists; Male; Mice; Mice, Inbred Strains; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Seizures

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Histamine; Histamine Antagonists; Hypoglycemia; Hypothalamus; Insulin; Kinetics; Male; Methylhistamines; Methylhistidines; Piperidines; Pituitary Hormones, Anterior; Prolactin; Rats; Rats, Wistar; Receptors, Histamine; Receptors, Histamine H3; Restraint, Physical; Stress, Physiological

In superfused mouse striatal slices preincubated with [3H]dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mumol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [3H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H3 agonist R-(-)-alpha-methylhistamine; it was not affected by the H1 antagonist dimetindene and the H2 antagonist ranitidine but abolished by the H3 antagonist thioperamide. Tritium overflow evoked by Ca2+ ions (introduced into Ca(2+)-free, K(+)-rich medium containing tetrodotoxin) was not affected by histamine 10 mumol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.

Topics: Animals; Calcium; Corpus Striatum; Dopamine; Electric Stimulation; Histamine; Histamine Agonists; In Vitro Techniques; Male; Methylhistamines; Mice; Mice, Inbred Strains; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Stereoisomerism; Synapses; Tritium

1. The influence of epithelium on the effects of H3-histamine receptor agonist (R)alpha-methylhistamine [(R)alpha-MeHist] on airways was investigated on the guinea-pig perfused bronchioles. 2. In preparations under resting tone, removal of the bronchiolar epithelium or treatment with the cyclo-oxygenase inhibitor indomethacin (10(-5) M) increased the constriction induced by histamine and acetylcholine in a concentration-dependent manner without an alteration of the K(+)-induced contraction. 3. In this preparation (R)alpha-MeHist induced a concentration-dependent bronchodilatation which was antagonized in a competitive manner by thioperamide (an H3-antagonist) with a pA2 value of 8.6. 4. This bronchodilatation was reversed to a low concentration-dependent constriction after either removal of the epithelium or treatment with indomethacin (10(-5) M) but was unaffected by both 10(-5) M tranylcypromine (an inhibitor of PGI2 synthesis) and 5 x 10(-5) M NG-nitro-L-arginine methyl ester (an inhibitor of NO synthesis). 5. It is suggested that, in guinea-pig perfused bronchioles (R)alpha-MeHist induces an epithelium-dependent relaxation via the release of metabolite(s) of arachidonic acid.

Topics: Acetylcholine; Animals; Anticonvulsants; Arginine; Bronchi; Bronchodilator Agents; Epithelium; Female; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Indomethacin; Male; Methylhistamines; Muscle Relaxation; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Papaverine; Perfusion; Piperidines; Prostaglandins; Receptors, Histamine H3; Tranylcypromine

In a companion paper (Serafin et al. 1992) we have demonstrated in vitro that histamine depolarizes three previously described medial vestibular nucleus neuron (MVNn) types (Serafin et al. 1991a, b). It has also been shown that this effect was exclusively mediated through postsynaptic H2 receptors. All the same, the eventual contribution of presynaptic H3 receptors to the physiological response of the MVNn to histamine remained an open question since, during the slicing procedure, any histaminergic axons projecting to the vestibular nuclei would have been interrupted. This rendered our study of H3-mediated effects of histamine difficult. Hence, in the present in vivo study our aim was three-fold: (1) to investigate the presence of H3 receptors at the vestibular nuclei level; (2) to evaluate the functional importance of MVNn H2 receptors; and (3) to explore whether H3 ligands, when injected intraperitoneally (i.p.), could modulate dynamic vestibular functions. In order to address the first two questions, we investigated postural changes induced by perfusion of the guinea-pig's vestibular nuclear complex with specific ligands of the H2 and H3 receptors. Our data extend the conclusions of our in vitro study and suggest that lateral vestibular nuclei neurons and the MVNn are endowed with both H2 and H3 receptors. Our results indicate furthermore that histamine can modulate, quite effectively, static vestibular reflexes. Finally, the present study demonstrates that i.p. injection of thioperamide, an H3 antagonist, induces a significant decrease in the horizontal vestibular-ocular reflex gain and, by contrast to most of the clinically used antihistaminics, has no detrimental effect on the alertness level. Our results may thus lead to clinical testing and use of H3 antagonists as antivertigo or anti motion-sickness drugs.

Topics: Animals; Anticonvulsants; Cimetidine; Electroencephalography; Guinea Pigs; Impromidine; Injections, Intraperitoneal; Perfusion; Piperidines; Posture; Receptors, Histamine; Reflex, Vestibulo-Ocular; Vestibular Nuclei

In the brain, the H3 type of histamine receptor has a pre-synaptic autoreceptor inhibitory role which regulates neuronal release and synthesis of histamine. To examine the interaction of the selective H3 receptor antagonist thioperamide with H3 receptors in the brain in vivo, we have used a functional and non-functional measurement of H3 receptor occupancy. In three species (rat, guinea-pig and mouse) peripheral administration of thioperamide caused dose-related increases in histamine turnover in the cerebral cortex (whole brain was examined in the mouse) and, in the same tissues, inhibited the ex vivo binding of the selective H3 receptor agonist [3H](R)-alpha-methylhistamine ([3H]-RAMH). The peak effect of thioperamide to inhibit ex vivo binding of [3H]RAMH was observed approximately 30 min after i.p. administration, whilst the maximum increase in histamine turnover did not occur until after at least 100 min. At a pretreatment time of 30 min, the ED50 of thioperamide to inhibit ex vivo binding of [3H]RAMH binding in the rat, guinea-pig and mouse brain was found to be 2.0 +/- 0.2, 4.8 +/- 0.6 and 2.6 +/- 0.3 mg/kg (mean +/- SEM, N = 4), respectively. We have also examined the effect of peripheral administration of RAMH on ex vivo binding of [3H]RAMH in rat cortex. Qualitatively and quantitatively similar results to those of thioperamide were observed following i.p. administration of RAMH to rats (ED50 = 3.9 +/- 0.4 mg/kg, mean +/- SEM, N = 4). An effect of RAMH on histamine turnover in rat cortex could not be determined as this compound displayed significant cross-reactivity with the antibodies used in the radioimmunoassay to measure histamine and telemethylhistamine. These data indicate that, following peripheral administration, both thioperamide and RAMH penetrate the brain where they can subsequently interact with H3 receptors. It would appear that binding of thioperamide to H3 receptors is linked with a concomitant increase in histamine turnover in the brain. In conclusion, the ex vivo binding technique, particularly when coupled with measurement of histamine turnover, should provide a valuable means for investigating the ability of any peripherally administered compound to cross the blood-brain barrier and subsequently interact with histamine H3 receptors.

Topics: Animals; Brain Chemistry; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Male; Methylhistamines; Mice; Piperidines; Rats; Receptors, Histamine; Receptors, Histamine H3

1. Thioperamide (TP), an imidazole and a highly potent, specific antagonist of the histamine H3 receptor, inhibited the secretion of cortisol from bovine isolated adrenocortical cells (IC50 0.20 microM) and in the rat (5 mg kg-1) prevented both basal and stress-induced secretion of corticosterone. 2. In adrenocortical microsomes, low affinity binding of [3H]-histamine (KD 27.7 microM) was potently inhibited by TP (Ki 0.33 microM). 3. In adrenocortical microsomal membranes, both histamine and TP yielded type II difference absorption spectra, characteristic of the interaction between imidazole and cytochrome P450 enzymes. Dissociation constants for binding to P450, calculated from spectral data, were 15.9 microM and 1.5 mM for histamine, and 0.3 microM and 3.7 microM for TP. 4. In view of previously reported evidence for an intracellular mediator role of histamine in platelets, the present findings suggest a physiological role for histamine in the modulation of adrenal P450 monooxygenases that generate adrenocortical steroids. 5. The results suggest that direct adrenocortical inhibition by thioperamide at a non-H3 intracellular site must be taken into account in studies designed to elucidate functional roles of H3 receptors.

Topics: Adrenal Cortex; Animals; Binding Sites; Cattle; Corticosterone; Cytochrome P-450 Enzyme System; Histamine; Histamine Antagonists; Hydrocortisone; Male; Microsomes; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Spectrophotometry, Ultraviolet

1. The effect of (R)-alpha-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 microA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2. (R)-alpha-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-alpha-methylhistamine was dose-dependent (10-300 micrograms kg-1, i.v.) and was not seen at high intensities of stimulation. 3. (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 micrograms kg-1, i.v.), indicating that the effect of (R)-alpha-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4. The inhibition of CNS-induced hypertension by (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-1, i.v.), impromidine (ID50 = 0.22 mg kg-1, i.v.) and burimamide (ID50 = 6 mg kg-1, i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 micrograms kg-1, i.v.) and cimetidine (3 mg kg-1, i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-alpha-methylhistamine. 5. These results suggest that (R)-alpha-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.

Topics: Animals; Blood Pressure; Burimamide; Dose-Response Relationship, Drug; Electric Stimulation; Epinephrine; Guinea Pigs; Heart Rate; Histamine Agonists; Histamine Antagonists; Impromidine; Male; Medulla Oblongata; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Sympathetic Nervous System

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/-). Infusion of a histamine H1-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, and H3-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.

Topics: Animals; Brain; Feeding Behavior; Histamine; Histamine Antagonists; Infusions, Intravenous; Male; Piperidines; Rats; Rats, Wistar; Rats, Zucker; Receptors, Histamine H3

The histamine H3 receptor agonist (R)alpha-methylhistamine (MeHA) inhibited, in a nanomolar range, basal and carbachol-stimulated inositol phosphate formation in the human gastric tumoral cell line HGT1-clone 6. The inhibition was reversed by micromolar concentrations of the histamine H3 receptor antagonist thioperamide and was sensitive to cholera or pertussis toxin treatment. Using [3H]N alpha-MeHA as specific tracer, high affinity binding sites were demonstrated with a Bmax of 54 +/- 3 fmol/mg of protein and a KD of either 0.61 +/- 0.04 or 2.2 +/- 0.4 nM, in the absence or presence of 50 microM GTP[gamma]S, respectively. The binding sites were solubilized by Triton X-100 and prepurified by gel chromatography. They were separated from the histamine H2 receptor sites by filtration through Sepharose-famotidine and finally retained on Sepharose-thioperamide. The purified sites concentrated in one single silver-stained protein band of 70 kDa in SDS-polyacrylamide gel electrophoresis. They specifically bound [3H]N alpha-MeHA with a KD of 1.6 +/- 0.1 nM and a Bmax of 12,000 +/- 750 pmol/mg of protein. This corresponds to a 90,225-fold purification over cell lysate and a purity degree of 84%. Binding was competitively displaced by N alpha-MeHA (IC50 = 5.8 +/- 0.7 nM), (R) alpha-MeHA (IC50 = 9 +/- 1 nM), and thioperamide (IC50 = 85 +/- 10 nM), but not by famotidine (H2 antagonist) or by mepyramine (H1 antagonist). These findings provide the first evidence for solubilization, purification, and molecular mass characterization of the histamine H3 receptor protein and for the negative coupling of this receptor phosphatidylinositol turnover through a so far unidentified G protein.

Topics: Binding Sites; Carbachol; Cholera Toxin; Chromatography, Affinity; Chromatography, Gel; Guanosine 5'-O-(3-Thiotriphosphate); Histamine Antagonists; Humans; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Kinetics; Methylhistamines; Molecular Weight; Phosphatidylinositols; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Stomach Neoplasms; Tumor Cells, Cultured

1. The effect of agents which interact with the histamine H3 receptor on potassium-stimulated tritium release from slices of rat entorhinal cortex preloaded with [3H]-choline is described. We have examined the effects of the selective H3 receptor agonist, (R)-alpha-methylhistamine (RAMH), and a number of H3 receptor antagonists, including the selective compound thioperamide, on the potassium-stimulated release of tritium. 2. In the presence of mepyramine and ranitidine, RAMH (0.01-10 microM) inhibited potassium-stimulated tritium release in a concentration-dependent manner, EC50 = 0.11 microM. The maximum inhibition was approximately 50%. 3. Thioperamide displaced the RAMH concentration-response curve to the right yielding a pKB value of 8.4. There was no change in the maximum response to RAMH. 4. Other H3 receptor antagonists, including impromidine and burimamide, also caused rightwards displacement of the linear portion of the RAMH concentration-response curve. However, phenylbutanoylhistamine and betahistine, which are reported to be relatively potent H3 receptor antagonists, showed very low affinity. 5. Thioperamide (0.001-1 microM) alone enhanced the potassium-stimulated release of tritium in a concentration-dependent manner. Maximum effects were observed at 0.1-1 microM thioperamide, enhancing release by approximately 20%. 6. Results are discussed in terms of the regulatory role of H3 receptors on acetylcholine release and the possible existence of H3 receptor subtypes.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Hippocampus; Histamine Agonists; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Piperidines; Potassium; Pyrilamine; Ranitidine; Rats; Receptors, Histamine; Receptors, Histamine H3

The preparation of a representative group of derivatives of the known H3-antagonist thioperamide is described. Binding affinity for histamine H3-receptors of thioperamide and its derivatives, which were obtained by substitution on the imidazole ring, was measured on rat brain cortex synaptosomes. Competitive binding assays were performed with two different labelled ligands, the physiological agonist [3H]histamine ([3H]HA) and the potent H3-agonist N alpha-[3H]methyl-histamine ([3]NAMHA). We observed a remarkable difference in Ki values obtained versus the two labelled ligands, both for thioperamide and its derivatives. In particular, 5-methylthioperamide showed a considerable selectivity for the system recognized by [3H]NAMHA, being about 100 times more potent versus this system than versus the system recognized by [3H]HA. On the basis of these observations, we suggest that it is necessary to consider this difference in evaluating the affinity of new compounds for the H3-receptors.

Topics: Animals; Cerebral Cortex; In Vitro Techniques; Ligands; Piperidines; Rats; Rats, Wistar; Receptors, Histamine; Receptors, Histamine H3; Synaptosomes

A simple and rapid functional test system for the screening of histamine H3 ligands is described. It is based on the inhibitory effect of histamine H3 agonists on electrically-evoked contractile response of isolated guinea pig intestine. Whole jejunum segments are continuously stimulated maximally (15 V) by electrical pulses with a frequency of 0.1 Hz and a duration of 0.5 msec. The resulting twitches are recorded isotonically (1.0 g) and can be completely abolished by atropine (0.1 mcM).

Topics: Acetylcholine; Animals; Atropine; Drug Evaluation, Preclinical; Electric Stimulation; Guinea Pigs; Histamine Agonists; In Vitro Techniques; Isotonic Contraction; Jejunum; Ligands; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effects of the specific H3 agonist (R)-alpha-methylhistamine (alpha-MeHA) and the specific H3 antagonist thioperamide were examined on histamine release and acid secretion [( 14C]-aminopyrine (AP) accumulation) by isolated rabbit gastric glands. Thioperamide significantly enhanced basal histamine release from the glands (+50% at 30 min for 10(-7) M thioperamide; P less than 0.01), and this increase was prevented by alpha-MeHA. Histamine-elicited AP accumulation was increased by 18% (P less than 0.05) by 10(-7) M thioperamide and decreased by 70% (P less than 0.01) by 10(-6) M of the H2 antagonist ranitidine. Thioperamide alone significantly enhanced AP accumulation in a dose-dependent manner, whereas alpha-MeHA had no effect of its own on this accumulation. Thioperamide stimulation of basal AP accumulation was not modified by ranitidine but was 50% decreased by alpha-MeHA. Furthermore, carbachol-induced AP accumulation was decreased by alpha-MeHA and increased by thioperamide; the latter effect was not blocked by ranitidine. These findings support that H3 receptors pharmacologically distinct from H2 receptors are involved in the regulation of histamine-stimulated acid secretion. They further suggest that these gastric H3 receptors occur in the gastric glands as 1) H3 autoreceptors located on the histamine-secreting cells and acting to downregulate histamine release from these cells and 2) H3 (or H3-like) receptors located on the parietal cell and regulating in a negative manner the acid secretory process.

Topics: Aminopyrine; Animals; Carbachol; Gastric Mucosa; Histamine; Histamine Release; In Vitro Techniques; Male; Methylhistamines; Piperidines; Rabbits; Ranitidine; Receptors, Histamine H1

The effects of histamine H3 receptor activation [(R)alpha-methylhistamine] and blockade (thioperamide) on rat gastric secretion were determined in vivo and in vitro. (R)alpha-Methylhistamine (0.1-5 mumol/kg i.p.) did not modify secretory volume and acidity in pylorus-ligated rats; it did not affect basal acid secretion and the secretion stimulated by histamine, pentagastrin and 2-deoxy-D-glucose in the lumen-perfused stomach of anaesthetized rats, when administered by continuous infusion (0.01-1 mumol/kg/h) or bolus injection (0.05-25 mumol/kg). In this preparation, the H3 agonist increased acid secretion at doses of 3-25 mumol/kg i.v., the effect being antagonized by famotidine. In the isolated gastric fundus from immature rats both (R)alpha-methylhistamine (0.01-10 mumol/l) and thioperamide (0.01-1 mumol/l) were totally ineffective against both spontaneous and stimulated gastric secretion. These results suggest that histamine H3 receptors are unlikely to have a role in regulating gastric acid secretion in the rat.

Topics: Animals; Female; Gastric Mucosa; Methylhistamines; Piperidines; Rats; Rats, Wistar

Topics: Animals; Brain Stem; Cimetidine; Electric Stimulation; Eye Movements; Guanidines; Guinea Pigs; Head; Imidazoles; Impromidine; In Vitro Techniques; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H2; Reflex, Vestibulo-Ocular; Rotation; Vestibular Nuclei

Airway damage secondary to eosinophil activation is thought to contribute to the development of asthma. Using the fluorescent dye FURA-2 to measure the concentration of cytosolic calcium, we found that supernatants from anti-IgE-stimulated human lung mast cells increased cytosolic calcium in human eosinophils. We then examined the major mast cell mediators (histamine, PGD2, platelet-activating factor (PAF), eosinophil chemotactic factor of anaphylaxis (ECF-A), leukotriene (LT)C4 and LTB4) for their ability to increase cytosolic calcium in eosinophils. We found that both PAF (5 x 10(-9) to 5 x 10(-6) M) and PGD2 (two of five donors responsive at 1 x 10(-9) M) were potent stimuli for calcium mobilization. LTB4 (10(-8), 10(-7) M) and histamine were also active, although higher concentrations of histamine were required to see a response (3 x 10(-7) to 10(-5) M). LTC4, val-ECF-A, and ala-ECF-A were inactive. The effects of PGD2 and histamine were specific for eosinophils, although LTB4 and PAF increased calcium in both neutrophils and eosinophils. The histamine-induced increase in intracellular calcium was not blocked by the H1 or H2 antagonists pyrilamine or cimetidine (10(-4) M), respectively; however, the response to 10(-6) M histamine was completely blocked by the specific H3 antagonist thioperamide (10(-6) M). To evaluate the relative contribution of these stimulatory mast cell mediators on the calcium mobilizing activity in supernatants from anti-IgE-stimulated human lung mast cell (HLMC), we examined the effect of supernatants from HLMC pretreated with indomethacin and/or the 5-lipoxygenase pathway inhibitor MK886. These supernatants were added to FURA-2-loaded eosinophils that had been preincubated with thioperamide and/or the PAF antagonist WEB-2086. We found that the increase in eosinophil calcium in response to supernatants from anti-IgE-stimulated-HLMC was totally inhibited only when the mast cells were challenged in the presence of indomethacin and MK886, and the eosinophils were preincubated with thioperamide. WEB-2086 had little effect. When we examined the effect of these mediators on eosinophil secretory function, we found that PGD2 (not histamine) primed eosinophils for enhanced release of LTC4 in response to the calcium ionophore A23187. We conclude that the activation of eosinophils by PGD2 and other mast cell products may contribute to airways inflammation that is characteristic of asthma.

Topics: Azepines; Calcimycin; Calcium; Cytosol; Dinoprostone; Eosinophils; Histamine; Histamine Antagonists; Humans; In Vitro Techniques; Lung; Mast Cells; Neutrophils; Piperidines; Platelet Activating Factor; Prostaglandin D2; Secretory Rate; SRS-A; Triazoles

The effects of the histamine H3 receptor ligands thioperamide and (R)-alpha-methylhistamine on the histidine decarboxylase (HDC) activity and histamine content of mouse brain were examined. Thioperamide, a histamine H3 antagonist, significantly increased the HDC activity in the brain of ddY, W/Wv and ICR mice 2-6 hr after its intraperitoneal (i.p.) injection. On the other hand, (R)-alpha-methylhistamine, a histamine H3-receptor agonist, caused no significant change in the HDC activity. The whole brain histamine content of ddY mice decreased significantly to 60-70% of the control level 2-8 hr after injection of thioperamide (25 mg/kg, i.p.), but then increased to 90% of the control level 10 hr after the injection. These in vivo results showed that blockade of the presynaptic histamine H3-receptor, which causes release of presynaptic histamine, increased the HDC activity.

Topics: Animals; Brain; Histamine; Histamine Antagonists; Histidine Decarboxylase; Injections, Intraperitoneal; Male; Methylhistamines; Mice; Mice, Inbred Strains; Piperidines; Time Factors

In an attempt to assess the role of histamine H3 receptors in the control of gastric acid secretion, the effects of the selective histamine H3 receptor agonist, (R) alpha-methylhistamine and antagonist, thioperamide were evaluated in the conscious gastric fistula cat under basal conditions and against different stimuli. (R) alpha-methylhistamine (0.05-0.2 mumol/kg/h) was ineffective against spontaneous and dimaprit-induced acid secretion; it also did not reduce significantly pentagastrin-induced acid output, but caused a dose-dependent (0.05-0.1 mumol/kg/h) and significant inhibition of the acid response to 2-deoxy-D-glucose. Thioperamide (0.02-0.04 mumol/kg/h) did not modify spontaneous acid secretion, whereas it evoked a significant enhancement of the acid response to submaximal doses (50 mg/kg i.v.) of 2-deoxy-D-glucose. Thioperamide completely reversed the inhibitory effect of (R) alpha-methylhistamine against 2-deoxy-D-glucose-induced secretion, while leaving unaffected the inhibition induced by somatostatin. These data suggest that histamine H3 receptors may be involved in the control of acid secretion stimulated by indirectly acting secretagogues.

Topics: Animals; Cats; Female; Gastric Acid; Gastric Fistula; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

A series of histamine H3 receptor agonists and the H3 receptor antagonist thioperamide were tested in the isolated guinea pig duodenum, to investigate the role of this new receptor subtype in the intestinal contractility. At the same time the selectivity of the different compounds for the various histamine receptor subtypes was investigated. In the presence of famotidine (10(-6) M) and thioperamide (10(-5) M), histamine, N alpha-methylhistamine (NMH) and (R)-alpha-methylhistamine (alpha-MH) exerted a concentration-dependent contractile effect through activation of H1 receptors; the ratio of potency was histamine = NMH greater than alpha-MH (this last compound was approximately 500 times less potent). In the presence of pyrilamine (10(-6) M) and thioperamide (10(-5) M), histamine, dimaprit and impromidine caused a slight contractile effect, showing a high degree of tachyphylaxis; this effect was abolished by tetrodotoxin (10(-6) M) and by famotidine (10(-6) M). alpha-MH was ineffective up to 10(-4) M. The H2 receptor agonists dimaprit (10(-4) to 10(-3) M) and impromidine (10(-6) to 10(-5) M) caused a relaxant effect on the contraction elicited by acetylcholine (ACh), BaCl2 and electrical stimulation. This effect, which was unaffected by famotidine, was not mimicked by alpha-MH and not reversed by thioperamide (10(-5) M). In the presence of pyrilamine (109-6) M) and famotidine (10(-6) M), histamine, NMH and alpha-MH inhibited the twitch responses to electrical stimulation, with EC50 values of 1.17 x 10(-7), 6.76 x 10(-8) and 2.45 x 10(-8) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Duodenum; Electric Stimulation; Guinea Pigs; Histamine; Histamine Antagonists; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Piperidines; Receptors, Histamine H2; Synaptic Transmission

The effects of intracarotid (i.a.) administration of the histamine (HA) H3-receptor agonist (R)-alpha-methyl-histamine (alpha MeHA) and of the H3-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H3-drugs. Neither THIO (2.5 mg/kg) nor alpha MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. alpha MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and alpha MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicated that endogenous brain HA facilitates PRL and inhibits GH secretion.

Topics: Animals; Growth Hormone; Histamine Antagonists; Kinetics; Male; Methylhistamines; Morphine; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3

The role of histamine H3-receptors in the control of acetylcholine release from peripheral cholinergic neurons was evaluated in the isolated guinea pig ileum, previously loaded with 3H-choline. When tested in the presence of H1- and H2-blockade, histamine (0.1-100 mumol/l) and (R) alpha-methylhistamine (0.01-1 mumol/l) dose-dependently reduced the electrically-evoked choline outflow, with (R) alpha-methylhistamine being a partial agonist. Selective H3-receptor blocking drugs, thioperamide (0.1 mumol/l) and impromidine (0.1 mumol/l) reversed the histamine-induced inhibitory effect. These data suggest that intestinal cholinergic nerves are endowed with histamine H3-receptors whose activation produces an inhibitory effect upon acetylcholine release. The practical implications of these findings are obvious.

Topics: Acetylcholine; Animals; Electric Stimulation; Guanidines; Guinea Pigs; Histamine; Histamine Antagonists; Ileum; Imidazoles; Impromidine; Methylhistamines; Myenteric Plexus; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Tritium

The effects of the H3-agonist R-alpha-methylhistamine (R-alpha-MeHA) and the H3-antagonist thioperamide on the spontaneous and concanavalin A (ConA) induced histamine release from human mast cells were tested and compared with the effect of some H1- and H2-receptor active substances. R-alpha-MeHA (10(-9)-10(-7) M) exerted no effect on histamine release whereas thioperamide increased the spontaneous release at 10(-6)-10(-4) M but inhibited the ConA induced release in a narrow concentration range (10(-6)-10(-5) M). This enhancement might be taken as an indication of the existence of H3-receptor dependent autoregulation although presently other mechanism cannot be excluded.

Topics: Adenoids; Cimetidine; Concanavalin A; Guanidines; Histamine Antagonists; Humans; Hydroxyzine; Imidazoles; Impromidine; Mast Cells; Meclizine; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3

The histamine H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA, 10(-10) to 10(-5) M), caused a concentration-dependent inhibition of the sympathetic contractile response to electrical field stimulation of guinea pig isolated atria, but alpha-MeHA did not alter the basal tension or the contraction induced by exogenously applied norepinephrine. Blockade of H1 and H2 histamine receptors, and alpha- and beta-adrenoceptors failed to prevent the inhibitory effect of alpha-MeHA, whereas the specific H3 receptor antagonist, thioperamide, concentration dependently reversed the inhibitory effect of alpha-MeHA. At the concentration of 10(-7) M, which was effective for antagonizing the action of alpha-MeHA, thioperamide did not modify the sympathetic responses facilitated by the beta 2-adrenoceptor agonist, clenbuterol, or attenuated by the alpha 2-adrenoceptor agonist, clonidine. Our results suggest that H3 receptors exist on the cardiac sympathetic terminals, which may modulate adrenergic neurotransmission in guinea pig myocardium.

Topics: Animals; Chlorpheniramine; Clenbuterol; Clonidine; Dose-Response Relationship, Drug; Electric Stimulation; Evoked Potentials; Guinea Pigs; Heart; Heart Atria; In Vitro Techniques; Methylhistamines; Nerve Endings; Norepinephrine; Phentolamine; Piperidines; Propranolol; Ranitidine; Receptors, Histamine; Receptors, Histamine H3; Sympathetic Nervous System; Synaptic Transmission

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cardiovascular System; Consciousness; Guinea Pigs; Heart Rate; Histamine Antagonists; Methylhistamines; Piperidines; Receptors, Histamine; Receptors, Histamine H3

The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.

Topics: Animals; Drug Interactions; Histamine Antagonists; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mammillary Bodies; Methylhistamines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Sleep; Wakefulness

The purpose of this study was to examine the effects of thioperamide, a histamine H3 antagonist, on the locomotor activity and the brain histamine content in mast-cell-deficient W/Wv mice. Thioperamide (12.5 and 25 mg/kg) showed significant increase in the locomotor activity of W/Wv mice, measured by a photo-beam system, 1 hr after the intraperitoneal injection. However, more than 75 mg/kg of thioperamide showed not only the reduction of the locomotor activity but also the inhibition of motor coordination measured by the rotarod performance. The increase in the locomotor activity by thioperamide was blocked by i. p. pretreatment with (R)-alpha-methyl-histamine, an H3 agonist, or pyrilamine, an H1 antagonist, or zolantidine, an H2 antagonist. The brain histamine content was decreased by thioperamide (12.5-75.0 mg/kg), 1 hr after administration. Thus, the blockade of histamine H3 receptor by thioperamide showed the activation of locomotor activity of mice, which may be mediated by H1 and/or H2 receptors. The present data support the hypothesis that central histaminergic neurons may be involved in the control of state of wakefulness.

Topics: Animals; Benzothiazoles; Brain Chemistry; Dopamine; Histamine; Histamine Antagonists; Histamine H2 Antagonists; Mast Cells; Methylhistamines; Mice; Mice, Mutant Strains; Motor Activity; Phenoxypropanolamines; Piperidines; Pyrilamine; Receptors, Histamine H3; Thiazoles

The release of endogenous histamine (HA) from the hypothalamus of anesthetized rats was measured by in vivo microdialysis coupled with HPLC with fluorescence detection. Freshly prepared Ringer's solution was perfused at a rate of 1 microliter/min immediately after insertion of a dialysis probe into the medial hypothalamus, and brain perfusates were collected every 30 min into microtubes containing 0.2 M perchloric acid. The basal HA output was almost constant between 30 min and 7 h after the start of perfusion, with the mean value being 7.1 pg/30 min. Thus, the extracellular HA concentration was assumed to be 7.8 nM, by a calculation from in vitro recovery through the dialysis membrane. Perfusion with a high K+ (100 mM)-containing medium increased the HA output by 170% in the presence of Ca2+. Systemic administration of either thioperamide (5 mg/kg, i.p.), a selective H3 receptor antagonist, or metoprine (10 mg/kg, i.p.), an inhibitor of HA-N-methyltransferase, caused an approximately twofold increase in the HA output 30-60 min after treatment. The combined treatment with thioperamide and metoprine produced a marked increase (650%) in the HA output. The HA output decreased by approximately 70% 4-5 h after treatment with alpha-fluoromethylhistidine (alpha-FMH; 100 mg/kg, i.p.), an inhibitor of histidine decarboxylase. Furthermore, the effect of combined treatment with thioperamide and metoprine was no longer observed in alpha-FMH-treated rats. These results suggest that both HA-N-methyltransferase and H3 autoreceptors are involved in maintaining a constant level of extracellular HA and that their blockade effectively results in a higher activity level of the endogenous histaminergic system in the CNS.

Topics: Animals; Chromatography, High Pressure Liquid; Dialysis; Fluorescence; Histamine N-Methyltransferase; Histamine Release; Histidine Decarboxylase; Hypothalamus; Male; Methylhistidines; Piperidines; Potassium; Rats; Rats, Inbred Strains

Using an in vivo intracerebral microdialysis method coupled with an HPLC-fluorometric method, we investigated the extracellular level of endogenous histamine in the anterior hypothalamic area of urethane-anaesthetized rats. The basal rate of release of endogenous histamine in the anterior hypothalamic area measured by this method was 0.09 +/- 0.01 pmol/20 min. When the anterior hypothalamic area was depolarized by infusion of 100 mM K+ through the dialysis membrane or electrical stimulation at 200 mu A was applied through an electrode implanted into the ipsilateral tuberomammillary nucleus, histamine release increased to 175% and 188%, respectively, of the basal level. These increases were completely suppressed by removal of extracellular Ca2+. The basal release of histamine was also suppressed after infusion of 10(-6) M tetrodotoxin or i.p. administration of 100 mg/kg of alpha-fluoromethylhistidine. On the other hand, 3-fold increase in the basal release was observed after i.p. administration of 5 mg/kg thioperamide. These results clearly indicate that both the basal and evoked release of histamine measured by our method are of neuronal origin.

Topics: Animals; Anterior Hypothalamic Nucleus; Calcium; Chromatography, High Pressure Liquid; Dialysis; Histamine Release; Histidine Decarboxylase; Male; Methylhistidines; Neurons; Piperidines; Rats; Rats, Inbred Strains; Tetrodotoxin

The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with (3H)choline. In the presence of H1 and H2 blockade, histamine (10(-7)-10(-4) M) and (R)-alpha-methylhistamine (10(-8)-10(-6) M) inhibited the electrically-evoked acetylcholine release, being (R)-alpha-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-alpha-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors.

Topics: Acetylcholine; Animals; Guinea Pigs; Histamine Antagonists; Ileum; Methylhistamines; Myenteric Plexus; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Tritium

We investigated the possible involvement of H3 receptor in the control of gastric acid secretion in the conscious cat provided with a gastric fistula [main stomach (MS)] and a denervated Heidenhain pouch (HP). Intravenous infusion of the selective H3 agonist (R)-alpha-methylhistamine at 3, 10, and 30 nmol.kg-1.h-1 induced a dose-related inhibition of pentagastrin-stimulated gastric acid output. Maximal inhibition in MS (48 +/- 3%, P less than 0.01) and HP (36 +/- 5%, P less than 0.01) was obtained with 30 nmol.kg-1.h-1. This dose also significantly inhibited peptone meal-induced gastric acid output by 38 +/- 4 and 46 +/- 8% (P less than 0.01) in MS and HP, respectively. These inhibitions were completely prevented by 10 nmol.kg-1.h-1 iv of the selective H3 receptor antagonist thioperamide. On the other hand, (R)-alpha-methylhistamine was without any effect on histamine-stimulated gastric acid output, whereas thioperamide produced a slight but not significant increase of this output in contrast to the H2 receptor antagonist ranitidine, which showed a strong inhibitory effect. These findings suggest that pentagastrin- or meal-induced gastric acid secretion involves an H3 receptor pharmacologically distinct from the H2 receptor.

Topics: Animals; Cats; Dietary Proteins; Dose-Response Relationship, Drug; Gastric Acid; Gastric Juice; Histamine; Kinetics; Methylhistamines; Pentagastrin; Piperidines; Receptors, Histamine; Receptors, Histamine H3

Histamine elicited dose-dependent accumulation of [3H]inositol phosphates in type-2 astrocytes, but not in type-1 astrocytes. The ED50 was about 2.4 x 10(-6) M and the maximal response was obtained at 10(-4) M. This response was dose-dependently inhibited by H1-antagonists, mepyramine and D- and L-chlorpheniramine. Furthermore, D- and L-chlorpheniramine showed stereoselectivity in the inhibition. On the other hand, an H2-antagonist, famotidine, and an H3-antagonist, thioperamide, did not inhibit the response. These results indicate that histamine stimulates accumulation of inositol phosphates in type-2 astrocytes via H1-receptors.

Topics: Animals; Astrocytes; Cells, Cultured; Chlorpheniramine; Famotidine; Histamine; Inositol Phosphates; Piperidines; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Histamine

We investigated the contraction responses of isolated guinea-pig ileum preparations under several conditions of electrical field stimulation. Histamine H3-agonists caused a dose-dependent inhibition of both cholinergic and nonadrenergic noncholinergic (NANC) responses (pD2 of histamine, 7.3; N alpha-methylhistamine, 8.4; (R)-alpha-methylhistamine, 8.3); H3-antagonists blocked this inhibition (pA2 of impromidine, 7.2; thioperamide, 8.5). Our results indicate that H3-receptors are present on both cholinergic and NANC nerves in the myenteric plexus and that the preparation can be used as a rapid and simple test system for histamine H3-receptors.

Topics: Animals; Atropine; Autonomic Nervous System; Electric Stimulation; Guanidines; Guinea Pigs; Histamine; Ileum; Imidazoles; Impromidine; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Parasympathetic Nervous System; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Tetrodotoxin

1. The effect of the selective histamine H3-receptor agonist R-(alpha)-methylhistamine has been investigated on the contractile responses of the longitudinal smooth muscle of guinea-pig ileum elicited by electrical field stimulation of acetylcholine release from myenteric nerve endings. 2. R-(alpha)-methylhistamine produced a concentration-dependent (EC50 = 1.4 +/- 0.2 x 10(-8) M) inhibition of the response to electrical field stimulation which was insensitive to inhibition by mepyramine (1 microM) and tiotidine (2.4 microM). 3. This response to R-(alpha)-methylhistamine could be inhibited in a competitive fashion by a range of H3-receptor antagonists including thioperamide (KB = 1.1 nM), impromidine (KB = 65 nM), norburimamide (KB = 380 nM) and SKF 91486 (KB = 34 nM). Burimamide was also a potent inhibitor of this response but the Schild slope obtained (1.3) was significantly greater than unity. 4. The estimated KB values were all within a factor of three of those values reported for the histamine H3-receptor mediating inhibition of histamine release in rat cerebral cortex. 5. These data suggest that the histamine receptor mediating inhibition of cholinergic neurotransmission by R-(alpha)-methylhistamine in guinea-pig ileum is the same as the H3-receptor present in rat cerebral cortex.

Topics: Animals; Electric Stimulation; Female; Guanidines; Guinea Pigs; Ileum; Imidazoles; Impromidine; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Pentolinium Tartrate; Piperidines; Receptors, Histamine; Receptors, Histamine H3

Rat brain cortex slices or synaptosomes preincubated with 3H-serotonin were superfused with physiological salt solution (which, in the case of slices, contained citalopram, an inhibitor of serotonin uptake), and the effects of histamine and related drugs on the evoked tritium overflow were studied. The electrically (3 Hz) evoked tritium overflow from slices was inhibited by histamine and the H3 receptor agonists R-(-)-alpha-methylhistamine and N alpha-methylhistamine (pIC12.5 values: 6.41, 7.28 and 6.12, respectively), but not affected by the H1 receptor agonist 2-(2-thiazolyl)ethylamine and the H2 receptor agonist dimaprit (each at 10 mumol/l). The concentration-response curve for histamine was shifted to the right by the H3 receptor antagonists impromidine, burimamide and thioperamide (apparent pA2 values: 7.45, 5.97 and 7.88, respectively); the concentration-response curve of serotonin for its inhibitory effect on the electrically evoked overflow was not affected by the three drugs (apparent pA2 values: less than 5.5, less than 5.5 and less than 6.5). Given alone, impromidine, thioperamide and a low concentration of burimamide facilitated the electrically evoked overflow. In slices superfused with K(+)-rich, Ca2(+)-free solution containing tetrodotoxin throughout and in synaptosomes superfused with Ca2(+)-free solution, histamine inhibited the overflow evoked by introduction of Ca2+ (in synaptosomes, simultaneously with an increased amount of K+). In either tissue, the effect of histamine was counteracted by thioperamide. The results provide evidence that exogenous and probably also endogenous histamine inhibits serotonin release in the rat brain cortex via presynaptic histamine H3 receptors.

Topics: Animals; Burimamide; Calcium; Cerebral Cortex; Electric Stimulation; Guanidines; Histamine; Imidazoles; Impromidine; In Vitro Techniques; Male; Methylhistamines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Serotonin; Synaptosomes; Tritium

Manipulating histamine endogenously, its effects on brain functions were assessed in rats. alpha-Fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, elicited feeding (P less than 0.01) after intra-third cerebroventricular infusion at the early light phase when hypothalamic histamine was normally highest. No periprandial drinking was observed. The effect of FMH was attenuated, and thioperamide, an antagonist of auto-inhibitory effects on both histamine synthesis and release at presynaptic H3-receptor, conversely suppressed food intake (P less than 0.05), when these probes were carried out during the minimum histamine level early in the dark period. Bilateral microinfusion of FMH into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) selectively induced feeding, but the infusion into the remaining sites of the hypothalamus had no effect. These data show that neuronal histamine plays a physiological role in feeding suppression through the VMH and the PVN in the rat.

Topics: Animals; Brain Chemistry; Drinking Behavior; Feeding Behavior; Histamine; Histidine Decarboxylase; Hypothalamus; Injections, Intraventricular; Male; Neurons; Piperidines; Rats; Rats, Inbred Strains

The effects of histamine H3-receptor ligands on sleep-waking parameters were studied in freely moving cats. Oral administration of (R)alpha-methylhistamine (alpha MHA), a H3-agonist, caused a significant increase in deep slow wave sleep while that of thioperamide, a H3-antagonist, enhanced wakefulness in a marked and dose-dependent manner. The arousal effects of thioperamide were prevented by pretreatment with alpha MHA or mepyramine, a H1-receptor antagonist. The findings support the hypothesis that the histaminergic neurons are critically involved in arousal mechanisms and suggest that H3-receptors play an active part in these mechanisms by regulating histamine transmission.

Topics: Animals; Arousal; Brain; Cats; Electroencephalography; Female; Ligands; Male; Methylhistamines; Neurons; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Reference Values; Sleep

To clarify whether monoamine neuron activity in the brain is regulated by histamine H3 receptors, the effects of a potent and selective H3 agonist, (R) alpha-methylhistamine and an antagonist, thioperamide, on monoamine metabolism were examined in the telencephalon, hypothalamus and brainstem of the rat and the whole mouse brain. Histamine turnover estimated from the pargyline-induced tele-methylhistamine accumulation decreased markedly with (R) alpha-methylhistamine administration (6.3 mg/kg i.p.) and increased with thioperamide administration (5 mg/kg i.p.) in all the brain regions examined. (R) alpha-Methylhistamine and thioperamide, at the doses tested, neither induced any significant changes in the levels of noradrenaline or 3,4-dihydroxyphenylacetic acid nor had any significant influence on the alpha-methyl-p-tyrosine-induced declines of the noradrenaline and dopamine levels in all the brain regions examined. However, thioperamide significantly decreased the dopamine level only in the rat telencephalon. In general, thioperamide increased 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios and pargyline-induced 5-HT accumulation. However, (R) alpha-methylhistamine affected neither the 5-HT nor the 5-HIAA level. The pargyline-induced 5-HT accumulation was slightly enhanced by (R) alpha-methylhistamine in the whole mouse brain. The enhancement by thioperamide of pargyline-induced 5-HT accumulation was not inhibited by (R) alpha-methylhistamine. These results suggest that H3 receptors have no important roles in the regulation of monoaminergic activity in contrast with their regulatory function in histaminergic activity. In addition, thioperamide at high doses may enhance 5-HT turnover independently of H3 receptors.

Topics: Animals; Biogenic Monoamines; Brain; Male; Methylhistamines; Mice; Mice, Inbred Strains; Pargyline; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3

The effects of a histamine H3-receptor antagonist on the bronchoconstrictor response to antigen challenge were studied in sensitized guinea pigs. We monitored airway opening pressure as an index of airway caliber, and the provocative dose of intravenous ovalbumin (OA) required to produce 200% increase in airway opening pressure (PD200) was determined. Animals were pretreated with propranolol to inhibit adrenergic bronchodilation. OA (1 to 100 micrograms/kg intravenously) challenge caused significant bronchoconstriction with a PD200 of 28.8 micrograms/kg (geometric mean). The selective H3-antagonist, thioperamide (5 mg/kg intraperitoneally), significantly enhanced the OA-induced bronchoconstriction with the PD200 value decreased to 4.0 micrograms/kg (p less than 0.001). The H2-antagonist, cimetidine (10 mg/kg intraperitoneally), had no significant effect on OA-induced response (PD200, 18.2 micrograms/kg). The H1-antagonist, mepyramine (10 mg/kg intraperitoneally), almost completely blocked the effect of OA, suggesting that OA-induced bronchoconstrictor responses are histamine (H1 receptor) mediated. Thioperamide did not alter the dose-response curve to exogenous histamine (0.3 to 3 micrograms/kg intravenously). We conclude that H3 receptors might play a role in regulation of antigen-induced response in the airways.

Topics: Animals; Antigens; Bronchoconstriction; Cimetidine; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Guinea Pigs; Histamine; Immunization; Male; Ovalbumin; Piperidines; Pyrilamine; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Skin Tests

The H3-histamine receptor provides feedback inhibition of histamine synthesis and release as well as inhibition of other neurotransmitter release. We have characterized this receptor by radioligand binding studies with the H3 agonist N alpha-[3H]methylhistamine ([3H]NAMHA). The results of [3H]NAMHA saturation binding and NAMHA inhibition of [3H]NAMHA binding were consistent with an apparently single class of receptors (KD = 0.37 nM, Bmax = 73 fmol/mg of protein) and competition assays with other agonists and the antagonists impromidine and dimaprit disclosed only a single class of sites. In contrast, inhibition of [3H]NAMHA binding by the specific high affinity H3 antagonist thioperamide revealed two classes of sites (KiA = 5 nM, BmaxA = 30 fmol/mg of protein; KiB = 68 nM, BmaxB = 48 fmol/mg of protein). Burimamide, another antagonist that, like thioperamide, contains a thiourea group, likewise discriminated between two classes of sites. In addition to differences between some antagonist potencies for the two receptors, there is a differential guanine nucleotide sensitivity of the two. The affinity of the H3A receptor for [3H] NAMHA was reduced less than 2-fold, whereas [3H]NAMHA binding to the H3B receptor was undetectable in the presence of guanosine 5'-O-(3-thiotriphosphate). The distinction between H3A and H3B receptor subtypes, the former a high affinity and the latter a low affinity thioperamide site, draws support from published in vitro data.

Topics: Animals; Binding Sites; Binding, Competitive; Brain Chemistry; Burimamide; Dimaprit; Guanidines; Guanosine 5'-O-(3-Thiotriphosphate); Histamine; Imidazoles; Impromidine; Male; Methylhistamines; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Thiourea; Tritium

We have investigated whether the histamine H3-receptors influence nonadrenergic noncholinergic (NANC) bronchoconstriction in guinea-pig in vivo. Atropine, propranolol, mepyramine and cimetidine were administered to block the effects of beta-adrenoceptor-, acetylcholine, H1- and H2-receptor-mediated responses, respectively. Vagal stimulation evoked a NANC bronchoconstrictor response. The selective H3-agonist, alpha-methylhistamine (alpha-MeHA, 1-10 mg/kg i.v.) did not alter basal respiratory insufflation pressure, but reduced the NANC bronchoconstrictor response to vagal stimulation in dose-dependent manner (with a maximal inhibition of 46.0 +/- 10.3%; mean +/- S.E. at 10 mg/kg) (P less than 0.02). Histamine itself also had a significant inhibitory effect on NANC responses with H1- and H2-blockade. The alpha-adrenoceptor antagonist phentolamine had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide blocked the inhibitory effect of alpha-MeHA. alpha-MeHA had no inhibitory effect on bronchoconstriction induced by exogenous substance P (5-25 micrograms/kg i.v.). We conclude that H3-receptors inhibit the release of transmitter from NANC nerves and that H3-receptors might play a role in regulation of neurogenic inflammatory responses in the airways.

Topics: Animals; Autonomic Nervous System; Blood Pressure; Bronchi; Guinea Pigs; Histamine; In Vitro Techniques; Male; Methylhistamines; Phentolamine; Piperidines; Receptors, Histamine; Respiration; Substance P

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.

Topics: Amygdala; Animals; Brain; Cerebral Cortex; Histamine; Histamine Antagonists; Kinetics; Male; Methylhistamines; Mice; Pargyline; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Tissue Distribution

Histamine 0.1 microM-0.1 mM increased adenylate cyclase activity five- to ten-fold in human fundic membranes, with a potency Ka = 3 microM. The histamine dose-response curve was mimicked by the H3 receptor agonist (R) alpha-MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine-induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50: famotidine (0.3 microM) greater than triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (beta 2-type), PGE2 and VIP. The Schild plot was linear for famotidine (P less than 0.01) with a regression coefficient r = 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT-1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long-lasting actions in the treatment of Zollinger-Ellison syndrome. The results also confirm and extend the previous observations that (R) alpha-MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.

Topics: Adenylyl Cyclases; Cyclic AMP; Famotidine; Gastric Fundus; Histamine; Histamine H2 Antagonists; Humans; In Vitro Techniques; Methylhistamines; Piperidines; Ranitidine; Receptors, Histamine; Stomach Neoplasms; Thiazoles; Triprolidine

The interaction of the potent histamine H3-receptor ligands i.e. (R)alpha-methylhistamine, an agonist, and thioperamide, an antagonist, with the three classes of cerebral histamine receptors was studied in vitro and in vivo. The histamine-induced stimulation of 3',5'-cyclic AMP accumulation in slices of guinea-pig hippocampus was not modified by thioperamide (up to 0.1 mM) and (R)alpha-methylhistamine stimulated cyclic AMP accumulation only at millimolar concentrations. Hence, both (R)alpha-methylhistamine and thioperamide were at least 100,000-fold more potent at H3- than at H1- or H2-receptors in brain. In vivo, the turnover of histamine in rat cerebral cortex, as determined from its depletion elicited by alpha-fluoromethylhistidine in a synaptosomal fraction was not modified by mepyramine and zolantidine but was markedly enhanced by thioperamide at a low dose (ED50 = 2 mg/kg). Thioperamide also elicited a long-lasting decrease in synaptosomal histamine and increase in radioimmunoassayable N tau-methylhistamine. In contrast, (R)alpha-methylhistamine markedly reduced cortical [3H]histamine synthesis (ED50 = 5 mg/kg). This long-lasting action was accompanied by an increase in synaptosomal histamine and a decrease in N tau-methylhistamine levels. These changes were compared with those in plasma drug levels. Hence the two H3-receptor ligands appear to modify the activity of cerebral histamine neurons markedly and in a long-lasting and opposite manner.

Topics: Animals; Brain; Brain Chemistry; Cyclic AMP; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine Decarboxylase; In Vitro Techniques; Male; Methylhistamines; Neurons; Piperidines; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3

The third histamine receptor was first identified on brain neurons and seems also to be present in other cells such as the lung mast cells. Hence the novel and potent H3 receptor agonist (R)-alpha-methylhistamine might find therapeutic applications in allergic diseases.

Topics: Animals; Brain; Guinea Pigs; In Vitro Techniques; Ligands; Lung; Mast Cells; Methylhistamines; Piperidines; Rats; Receptors, Histamine; Stereoisomerism; Structure-Activity Relationship

Serum albumin conjugates of histamine or tele-methylhistamine, a major catabolite, were prepared using 1,4-benzoquinone as the coupling agent and used to raise polyclonal antibodies in rabbits. The same reagent was used to prepare the [125I]iodinated tracer and treat tissue extracts submitted to the radioimmunoassays. The IC50 values of prederivatized histamine and tele-methylhistamine in the radioimmunoassays were 0.3 nM and 0.5 nM, respectively, whereas nonderivatized histamine or tele-methylhistamine, histidine, a variety of histamine derivatives, amines, etc., had at least 1,000-fold higher IC50 values. Application of the radioimmunoassays to nonpurified extracts of rat brain allowed the quantification of the two amine immunoreactivities in samples corresponding to less than 1 mg of hypothalamus. The tissue immunoreactivity corresponded to authentic histamine or tele-methylhistamine, as shown by (a) the parallel 125I-tracer displacement curves, (b) the similar elution patterns from HPLC columns, (c) the regional levels of histamine and tele-methylhistamine in brain, similar to those obtained with other methods, and (d) the clearcut effects of treatments with inhibitors of L-histidine decarboxylase or monoamine oxidase. The two radioimmunoassays appear as simple and sensitive tools to evaluate steady-state levels and turnover rates of histamine and tele-methylhistamine.

Topics: Animals; Brain Chemistry; Cerebral Cortex; Chromatography, High Pressure Liquid; Cross Reactions; Histamine; Histidine Decarboxylase; Male; Methylhistamines; Methylhistidines; Organ Specificity; Pargyline; Piperidines; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values; Tritium

The regulation of histamine release was studied on slices prepared from pieces of human cerebral cortex removed during neurosurgery and labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration induced [3H]histamine release, although to a lesser extent than from rat brain slices. Exogenous histamine reduced by up to 60% the K+-evoked release, with an EC50 of 3.5 +/- 0.5 X 10(-8) M. The H3-receptor antagonists impromidine and thioperamide reversed the histamine effect in an apparently competitive manner and enhanced the K+-evoked release, indicating a participation of endogenous histamine in the release control process. The potencies of histamine and the H3-receptor antagonists were similar to those of these agents at presynaptic H3-autoreceptors controlling [3H]histamine release from rat brain slices. It is concluded that H3-receptors control histamine release in the human brain.

Topics: Cerebral Cortex; Histamine; Histamine Release; Humans; Imidazoles; Impromidine; Piperidines; Potassium; Receptors, Histamine; Receptors, Histamine H3; Tritium

In contrast to cerebral histamine H1 and H2-receptors, histamine H3-receptors are presynaptically located on histamine-synthesizing nerve terminals (autoreceptors) and control the synthesis and release of the amine in cerebral neurons. Two imidazole derivatives were designed to interact at H3-receptors: (R) alpha-methylhistamine (alpha-MeHA), a chiral agonist, and thioperamide, a competitive antagonist derived from imidazolyl piperidine, both display high selectivity and potency at nanomolar concentrations in vitro. (R) alpha-MeHA, being about 15 times as potent as histamine itself, constitutes, when tritiated, a suitable probe for the radioassay of H3-receptors. Outside the brain, H3-receptor sites could be detected in the lung. The availability of new ligands made it possible to assess in vivo the physiological role of central and peripheral H3-receptors. The agonist and the antagonist modified in opposite directions histamine synthesis in the lung as in the brain, confirming the presence of H3-receptors in this peripheral organ. A large part of lung histamine being present within mast-cells, it is likely that these cells are endowed with H3-receptors controlling the amine synthesis and, possibly, release. Therefore, the novel agents may be of great practical interest in the field of allergy and inflammation.

Topics: Animals; Brain; Cerebral Cortex; Guinea Pigs; Histamine; Histamine Release; In Vitro Techniques; Ligands; Lung; Methylhistamines; Piperidines; Rats; Receptors, Histamine

The third histamine receptor was first indentified on brain neurons and seems to be present in other cells such as lung mast cells. Hence the novel and potent H3-receptor agonist (R) alpha-methylhistamine might find therapeutic applications in allergic diseases.

Topics: Animals; Methylhistamines; Piperidines; Radioligand Assay; Rats; Receptors, Histamine; Receptors, Histamine H3